tag:theconversation.com,2011:/us/topics/gwas-29074/articlesGWAS – The Conversation2023-06-29T15:01:08Ztag:theconversation.com,2011:article/2084162023-06-29T15:01:08Z2023-06-29T15:01:08ZResearchers can learn a lot with your genetic information, even when you skip survey questions – yesterday’s mode of informed consent doesn’t quite fit today’s biobank studies<figure><img src="https://images.theconversation.com/files/534693/original/file-20230628-29-j4a0gl.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1999%2C1499&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Participants in biobank studies are often asked for broad consent to use their data.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/genetic-research-royalty-free-image/136810911">Science Photo Library - TEK IMAGE/Brand X Pictures via Getty Images</a></span></figcaption></figure><p>Imagine you agreed to be part of a new and exciting long-term research study to better understand human health and behavior. For the past few years, you’ve been visiting a collection site where you fill out some questionnaires about your health and daily activities. Research assistants take your height, weight and some other physical characteristics about you. Because you agreed to contribute your genetic data to the study, you also provided a saliva sample during your first visit.</p>
<p>Later, you see a news article reporting that researchers analyzing data from the study you’re participating in have <a href="https://www.vox.com/science-and-health/2018/8/23/17527708/genetics-genome-sequencing-gwas-polygenic-risk-score">found genetic variants</a> that predict the likelihood of someone completing college. You remember reading a long form when you consented to giving your data, but you can’t quite remember all the details. You know the study was about health, but how do these findings about genes and education have anything to do with health? Did they analyze your data specifically? What did they find? </p>
<h2>What are biobanks?</h2>
<p>Many scientific research studies collect data meant to answer a specific research question. For example, to study the genetics of diabetes, researchers might collect data on your blood pressure and lipid levels in addition to genetic data. But increasingly, scientists are collecting large amounts of data to be <a href="https://doi.org/10.1186/s12967-019-1922-3">kept in biobanks</a> – repositories that store genetic data and other biospecimens like blood, urine or tumor tissue to be used in a wide number of future studies.</p>
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<figcaption><span class="caption">Biobank data is often used to conduct genome-wide association studies, or GWAS.</span></figcaption>
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<p>Some biobanks, like the <a href="https://www.ukbiobank.ac.uk">UK Biobank</a>, link biospecimen data to other collected data, such as sexual behavior, medical history, weight, diet and lifestyle. Private companies <a href="https://theconversation.com/how-a-south-african-communitys-request-for-its-genetic-data-raises-questions-about-ethical-and-equitable-research-166940">like 23andMe</a> also obtain consent from their customers to have their data used in research efforts.</p>
<p><a href="https://scholar.google.com/citations?user=zCedU50AAAAJ&hl=en&oi=ao">As a researcher</a> interested in the intersection between <a href="https://www.robbeewedow.com">social behaviors and genetics</a>, I frequently have conversations with people who weren’t aware of how their genetic data is being used. They’re often surprised that the genetic data they consented to be used for research at a private company by using a DNA testing kit or at a biobank while visiting their local clinic might be used to study the genetics of <a href="https://doi.org/10.1126/science.aat7693">same-sex sexual behavior</a> or <a href="https://doi.org/10.1038/s41588-018-0309-3">risk-taking</a>. </p>
<p>In our newly published research, my colleagues and I found that even <a href="https://www.nature.com/articles/s41562-023-01632-7">choosing not to respond to survey questions</a> can reveal information about the population (we found that not responding to survey questions is correlated with a person’s education, health and income levels) if genetic data is available.</p>
<h2>Genetic data and informed consent</h2>
<p>The research that can be done with biobank data might sound scary, but it shouldn’t be. Genetic data, like the data used in our study, is de-identified. This means that it cannot be linked back to individual research participants, who remain anonymous. Further, genetic data for these sorts of genetic studies is used <a href="https://doi.org/10.1038/s43586-021-00056-9">at the aggregate level</a>, meaning it isn’t used to predict or evaluate any one particular individual’s responses or behaviors.</p>
<p>Researchers aren’t using genetic data to target individuals with certain genetic profiles. Almost all genetic research is used to better understand how health behaviors and other factors affect health and to figure out ways to improve outcomes. This goal is why most research participants agree to contribute their data to research in the first place: to help the world through science.</p>
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<figcaption><span class="caption">Many developments in human subject protections arose in response to unethical research.</span></figcaption>
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<p>The problem is whether research participants really understand how their data can be used. Many of the original ideas around the development of the <a href="https://doi.org/10.1186/s12910-019-0414-6">informed consent process and Institutional Review Boards</a>, or IRBs, intended to protect research participants from direct harm or privacy violations were based on the expectation that research studies would be addressing particular questions about a single subject, like cardiovascular disease or lung cancer. This focus was so as not to repeat unethical research atrocities like the infamous <a href="https://www.cdc.gov/tuskegee/timeline.htm">Tuskegee Syphilis Study</a>, where researchers did not tell participants, who were all Black men, that they had syphilis and withheld treatment that was already widely available and known to be highly effective.</p>
<p>But since genetic data is de-identified, it is <a href="https://www.hhs.gov/ohrp/node/4350/index.html">often considered exempt from full IRB review</a>, which is a protocol to ensure studies meet ethical standards and institutional policies. And the broad number of research questions that can be explored with biobanks, along with the amount and types of data collected, has made these original protections to ensure truly informed consent insufficient.</p>
<h2>Improving informed consent</h2>
<p>To be clear, biobanks are enormously important for public health research. They allow researchers to <a href="https://theconversation.com/people-dont-mate-randomly-but-the-flawed-assumption-that-they-do-is-an-essential-part-of-many-studies-linking-genes-to-diseases-and-traits-194793">link many different outcomes and variables</a> together to paint a critical overall picture of human health and behavior. And in contrast with the <a href="https://theconversation.com/most-americans-dont-realize-what-companies-can-predict-from-their-data-110760">personally identifiable online or phone data</a> that companies collect to show you targeted ads, biobanks collect de-identified data that is evaluated in aggregate.</p>
<p>In the age of vast data collection, ensuring that participants are aware of how their data can and cannot be used is necessary to ensure that biobanks are a transparent tool for global good. Biobanks can’t predict how a participant’s data will be used in the future, so it can be difficult for researchers and ethicists to bring back the “informed” part of “informed consent.” Even so, more needs to be done to earn the trust of the valuable research participants who contribute the data to improve science and the world.</p><img src="https://counter.theconversation.com/content/208416/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Robbee Wedow is a research fellow at AnalytiXIN, which is a consortium of health-data organizations, industry partners and university partners in Indiana primarily funded through the Lilly Endowment, IU Health and Eli Lilly and Company.</span></em></p>Biobanks collect and store large amounts of data that researchers use to conduct a wide range of studies. Making sure participants understand what they’re getting into can help build trust in science.Robbee Wedow, Assistant Professor of Sociology and Data Science, Purdue UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1947932022-11-21T13:15:49Z2022-11-21T13:15:49ZPeople don’t mate randomly – but the flawed assumption that they do is an essential part of many studies linking genes to diseases and traits<figure><img src="https://images.theconversation.com/files/496010/original/file-20221117-25-slwoe3.jpg?ixlib=rb-1.1.0&rect=110%2C96%2C4690%2C2134&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Statistical pitfalls in GWAS can result in misleading conclusions about whether some traits (like long horns or spotted skin, in the case of dinosaurs) are genetically linked.</span> <span class="attribution"><span class="source">@meanymoo</span>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p>The idea that <a href="https://doi.org/10.1002/0471667196.ess0209.pub2">correlation does not imply causation</a> is a fundamental caveat in epidemiological research. A classic example involves a hypothetical link between ice cream sales and drownings – instead of increased ice cream consumption causing more people to drown, it’s plausible that a third variable, summer weather, is driving up an appetite for ice cream and swimming, and hence opportunities to drown.</p>
<p>But what about correlations involving genes? How can researchers be sure that a particular trait or disease is truly genetically linked, and not caused by something else?</p>
<p>We are <a href="https://www.richardborder.com">statistical</a> <a href="https://scholar.google.com/citations?user=SPXgieEAAAAJ&hl=en">geneticists</a> who study the genetic and nongenetic factors that influence human variation. In our <a href="https://www.science.org/doi/10.1126/science.abo2059">recently published research</a>, we found that the genetic links between traits found in many studies might not be connected by genes at all. Instead, many are a result of how humans mate.</p>
<h2>Genome-wide association studies try to link genes to traits</h2>
<p>Because the genes you inherit from your parents remain unchanged throughout your life, with rare exception, it makes sense to assume that there is a causal relationship between certain traits you have and your genetics.</p>
<p>This logic is the basis for <a href="https://www.genome.gov/about-genomics/fact-sheets/Genome-Wide-Association-Studies-Fact-Sheet">genome-wide association studies, or GWAS</a>. These studies collect DNA from many people to identify positions in the genome that might be correlated with a trait of interest. For example, if you have certain forms of the <a href="https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet"><em>BRCA1</em> and <em>BRCA2</em> genes</a>, you may have an increased risk for certain types of cancer.</p>
<p>Similarly, there may be gene variants that play a role in whether or not someone has schizophrenia. The hope is to learn something about the complex mechanisms that link variation at the molecular level to individual differences. With a clearer understanding of the genetic basis of different traits, scientists would be better able to determine risk factors for related diseases. </p>
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<figcaption><span class="caption">GWAS studies seek to find genetic associations between individual traits.</span></figcaption>
</figure>
<p>Researchers have run <a href="https://doi.org/10.1093/nar/gky1120">thousands of GWAS to date</a>, identifying genetic variants associated with myriad diseases and disease-related traits. In many instances, researchers have identified genetic variants that affect more than one trait. This form of biological overlap, in which the same genes are thought to influence several apparently unrelated traits, is known as <a href="https://doi.org/10.1186/s13073-016-0332-x">pleiotropy</a>. For example, certain variants of the <a href="https://medlineplus.gov/genetics/gene/pah"><em>PAH</em> gene</a> can have <a href="https://medlineplus.gov/genetics/condition/phenylketonuria/">several distinct effects</a>, including altering skin pigmentation and causing seizures.</p>
<p>One way scientists assess pleiotropy is through <a href="https://doi.org/10.1038/ng.3604">genetic correlation analysis</a>. Here, geneticists investigate whether the genes associated with a given trait are associated with other traits or diseases by statistically analyzing large samples of genetic data. Over the past decade, genetic correlation analysis has become the primary method for assessing potential pleiotropy across fields as diverse as <a href="https://doi.org/10.1038/ng.3406">internal medicine</a>, <a href="https://www.thessgac.org">social science</a> and <a href="https://doi.org/10.1017/s0033291717002318">psychiatry</a>. </p>
<p>Scientists use the findings from genetic correlation analyses to figure out the potential shared causes of these traits. For instance, if <a href="https://doi.org/10.1126/science.aap8757">genes associated with bipolar disorders</a> also predict anxiety disorders, perhaps the two conditions may partially involve some of the same neural circuits or respond to similar treatments.</p>
<h2>Assortative mating and genetic correlation</h2>
<p>However, just because a gene is correlated with two or more traits doesn’t necessarily mean it causes them.</p>
<p>Virtually all the statistical methods researchers commonly use to assess genetic correlations <a href="https://doi.org/10.1046/j.1439-0388.2002.00356.x">assume that mating is random</a>. That is, they assume that potential mating partners decide who they will have children with based on a roll of the dice. In reality, many factors likely influence who mates with whom. The simplest example of this is geography – people living in different parts of the world are less likely to end up together than people living nearby.</p>
<p>We wanted to find out how much the assumption of random mating affects the accuracy of genetic correlation analyses. In particular, we focused on the potential confounding effects of <a href="https://doi.org/10.1038/s41562-018-0476-3">assortative mating</a>, or how people tend to mate with those who share similar characteristics with them. Assortative mating is a widely documented phenomenon seen across a broad array of traits, interests, measures and social factors, including <a href="https://doi.org/10.1002/ajhb.22917">height</a>, <a href="https://doi.org/10.2307/2095670">education</a> and <a href="https://doi.org/10.1016/j.biopsych.2019.06.025">psychiatric conditions</a>.</p>
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<figcaption><span class="caption">Humans do not mate randomly – rather, people tend to gravitate toward certain traits.</span></figcaption>
</figure>
<p>In <a href="https://doi.org/10.1126/science.abo2059">our study</a> we examined cross-trait assortative mating, whereby people with one trait (for example, being tall) tend to mate with people with a completely different trait (for example, being wealthy). From our database of 413,980 mate pairs in the U.K. and Denmark, we found evidence of cross-trait assortative mating for many traits – for instance, an individual’s time spent in formal schooling was correlated not only with their mate’s educational attainment, but also with many other characteristics, including height, smoking behaviors and risk for different diseases.</p>
<p>We found that taking into consideration the similarities across mates could strongly predict which traits would be considered genetically linked. In other words, just based on how many characteristics a pair of mates shared, we could identify around 75% of the presumed genetic links between these traits – all without sampling any DNA.</p>
<h2>Genetic correlation does not imply causation</h2>
<p>Cross-trait assortative mating shapes the genome. If people with one heritable trait tend to mate with people with another heritable trait, then these two distinct characteristics will become genetically correlated to each other in subsequent generations. This will happen regardless of whether or not these traits are truly genetically linked to each other.</p>
<p>Cross-trait assortative mating means that the genes you inherit from one parent will be correlated with those you inherit from the other. How people mate is not random, violating the key assumption behind genetic correlation analyses. This inflates the genetic association between traits that aren’t truly linked together by genes.</p>
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<a href="https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of dinosaurs with and without long horns or spiked backs." src="https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=424&fit=crop&dpr=1 600w, https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=424&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=424&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=533&fit=crop&dpr=1 754w, https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=533&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/495756/original/file-20221116-21-hyom6p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=533&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">If dinosaurs with long horns preferentially mate with dinosaurs with spiked backs, genes for both of these traits can become associated with each other in subsequent generations even though the same gene doesn’t code for them.</span>
<span class="attribution"><span class="source">Aaqilah M</span>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
</figcaption>
</figure>
<p>Recent studies corroborate our findings. Earlier this year, researchers computed genetic correlations using a method that examines the association between the <a href="https://doi.org/10.1038/s41588-022-01062-7">traits and genes of siblings</a>. The genetic links between traits influenced by cross-trait assortative mating were substantially weakened.</p>
<p>But without accounting for cross-trait assortative mating, using genetic correlation estimates to study the biological pathways causing disease can be misleading. Genes that affect only one trait will appear to influence multiple different conditions. For example, a genetic test designed to assess the risk for one disease may incorrectly detect vulnerability for a broad number of unrelated conditions.</p>
<p>The ability to measure variation across individuals at the genetic and molecular level is truly a feat of modern science. However, genetic epidemiology is still an observational enterprise, subject to the same caveats and challenges facing other forms of nonexperimental research. Though our findings don’t discount all genetic epidemiology research, understanding what genetic studies are truly measuring will be essential to translate research findings into new ways to treat and assess disease.</p><img src="https://counter.theconversation.com/content/194793/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Border receives funding from the National Institutes of Health.</span></em></p><p class="fine-print"><em><span>Noah Zaitlen receives funding from the NIH, NSF, DoD, and CZI. </span></em></p>People don’t randomly select who they have children with. And that means an underlying assumption in research that tries to link particular genes to certain diseases or traits is wrong.Richard Border, Postdoctoral Researcher in Statistical Genetics, University of California, Los AngelesNoah Zaitlen, Professor of Neurology and Human Genetics, University of California, Los AngelesLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1859972022-09-12T12:15:12Z2022-09-12T12:15:12ZUncovering the genetic basis of mental illness requires data and tools that aren’t just based on white people – this international team is collecting DNA samples around the globe<figure><img src="https://images.theconversation.com/files/483545/original/file-20220908-9329-hl0h3j.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2419%2C1238&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Ethical and equitable scientific collaboration could help increase the genetic diversity of genomic data.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/scientists-on-world-map-discussing-during-royalty-free-illustration/1322363700">gmast3r/iStock via Getty Images Plus</a></span></figcaption></figure><p>Mental illness is a growing public health problem. In 2019, an estimated <a href="https://www.who.int/news-room/fact-sheets/detail/mental-disorders">1 in 8 people around the world</a> were affected by mental disorders like depression, schizophrenia or bipolar disorder. While scientists have long known that many of these disorders run in families, their genetic basis isn’t entirely clear. One reason why is that the majority of existing genetic data used in research is overwhelmingly from white people.</p>
<p>In 2003, the Human Genome Project generated the first “reference genome” of human DNA from a combination of samples donated by <a href="https://www.statnews.com/2019/03/11/human-reference-genome-shortcomings/">upstate New Yorkers</a>, all of whom were of European ancestry. Researchers across many biomedical fields still use this reference genome in their work. But it doesn’t provide a complete picture of human genetics. Someone with a different genetic ancestry will have a number of <a href="https://www.yourgenome.org/facts/what-is-genetic-variation/">variations</a> in their DNA that aren’t captured by the reference sequence. </p>
<p>When most of the world’s ancestries are not represented in genomic data sets, studies won’t be able to provide a true representation of how diseases manifest across all of humanity. Despite this, ancestral diversity in genetic analyses hasn’t improved in the two decades since the Human Genome Project announced its first results. As of June 2021, <a href="https://doi.org/10.1038/s41591-021-01672-4">over 80%</a> of genetic studies have been conducted on people of European descent. Less than 2% have included people of African descent, even though these individuals have the <a href="https://doi.org/10.1073/pnas.1017511108">most genetic variation</a> of all human populations.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1492867130622193664"}"></div></p>
<p>To uncover the <a href="https://doi.org/10.1038/s41586-022-04556-w">genetic factors</a> driving mental illness, <a href="https://scholar.google.com/citations?user=lWu2u8kAAAAJ&hl=en">I</a>, <a href="https://scholar.google.com/citations?view_op=list_works&hl=en&hl=en&user=iS0IoKgAAAAJ&sortby=pubdate">Sinéad Chapman</a> and our colleagues at the Broad Institute of MIT and Harvard have partnered with collaborators around the world to launch <a href="https://www.broadinstitute.org/stanley-center-psychiatric-research/stanley-global">Stanley Global</a>, an initiative that seeks to collect a more diverse range of genetic samples from beyond the U.S. and Northern Europe, and train the <a href="https://doi.org/10.1038/s41588-022-01095-y">next generation of researchers</a> around the world. Not only does the genetic data lack diversity, but so do the tools and techniques scientists use to sequence and analyze human genomes. So we are implementing a new sequencing technology that addresses the inadequacies of previous approaches that don’t account for the genetic diversity of global populations.</p>
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<figcaption><span class="caption">Ethically and equitably expanding the diversity of genomics data can help improve care and reduce disparities.</span></figcaption>
</figure>
<h2>Global partnerships for global data</h2>
<p>To study the genetics of psychiatric conditions, researchers use data from <a href="https://www.genome.gov/about-genomics/fact-sheets/Genome-Wide-Association-Studies-Fact-Sheet">genome-wide association studies</a> that compare the genetic variations between people with and without a particular disease. However, these data sets are mostly <a href="https://doi.org/10.1038/s41591-021-01672-4">based on people of European ancestry</a>, largely because research infrastructure and funding for large-scale genetics studies, and the scientists conducting these studies, have historically been concentrated in Europe and the United States.</p>
<p>One way to close this gap is to sequence genetic data from diverse populations. My colleagues and I are working in close partnership with geneticists, statisticians and epidemiologists in 14 countries across four continents to study the DNA of tens of thousands of people of African, Asian and Latino ancestries who are affected by mental illness. We work together to recruit participants and collect DNA samples that are sequenced at the Broad Institute in Massachusetts and shared with all partners for analysis.</p>
<p><iframe id="ZIVeg" class="tc-infographic-datawrapper" src="https://datawrapper.dwcdn.net/ZIVeg/4/" height="400px" width="100%" style="border: none" frameborder="0"></iframe></p>
<p><a href="https://doi.org/10.1038/d41586-021-01795-1">Prioritizing the voices and priorities</a> of local communities and scientists is foundational to our work. All partners have joint ownership of the project, including decision-making and sample and data ownership and control. To do this, we build relationships and trust with the local communities we are studying and the local university leaders and scientists with whom we are partnering. We work to understand local cultures and practices, and adapt our collection methods to ensure study participants are comfortable. For example, because there are different cultural sensitivities around providing saliva and blood samples, we have adapted our practices by location to ensure study participants are comfortable.</p>
<p>We also freely share knowledge and materials with our partners. There is a two-way exchange of information between the Broad Institute and local teams on study progress and results, enabling continual learning, teaching and unity between teams. We strive to meet each other where we are by exchanging practices and training scientists to support the development of locally grown and locally led research programs.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Researchers in the GINGER program looking at laptop together and smiling" src="https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=454&fit=crop&dpr=1 600w, https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=454&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=454&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=570&fit=crop&dpr=1 754w, https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=570&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/474777/original/file-20220719-18-mu7fdh.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=570&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The Global Initiative for Neuropsychiatric Genetics Education in Research (GINGER) program is focused on training the next generation of scientists.</span>
<span class="attribution"><a class="source" href="https://gingerprogram.org/">Global Initiative for Neuropsychiatric Genetics Education in Research</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
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<p>Our collaboration with African research groups provides a prime example of <a href="https://doi.org/10.1038/s41588-022-01095-y">our model</a>. For example, our African research colleagues are co-leaders on the grants that fund the lab equipment, scientists and other staff for projects based at their study sites. And we help to support the next generation of African geneticists and bioinformaticians through a <a href="https://www.broadinstitute.org/stanley-center-psychiatric-research/neurogap/global-initiative-neuropsychiatric-genetics-education-research-ginger">dedicated training program</a>.</p>
<h2>Analyzing variation</h2>
<p>Collecting samples from more diverse populations is only half of the challenge. </p>
<p>Existing genomic sequencing and analysis technologies do not adequately capture genetic variation across populations from around the world. That’s because these technologies were designed to detect genetic variations based on reference DNA from people of European ancestry, and they <a href="https://doi.org/10.1126/science.abg8871">reduce accuracy</a> when analyzing sequences that aren’t derived from the reference genome. When these tools are applied to genetic data from other populations, they <a href="https://doi.org/10.1016/j.ajhg.2021.03.012">fail to detect much of the rich variation</a> in their genomes. This can lead researchers to miss out on important biomedical discoveries. </p>
<p>To address this issue, we developed an approach to genome sequencing that can detect more genetic variation from populations around the world. It works by sequencing the <a href="https://www.genome.gov/genetics-glossary/Exome">exome</a> – the less than 2% of the genome that codes for proteins – in high detail, as well as sequencing the 98% of the genome that does not code for proteins in less detail.</p>
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<figcaption><span class="caption">Different types of sequencing methods have pros and cons.</span></figcaption>
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<p>This combined approach reduces the trade-offs geneticists often have to make in sequencing projects. <a href="https://medlineplus.gov/genetics/understanding/testing/sequencing/">High-depth whole genome sequencing</a>, which reads through the entire genome multiple times to get detailed data, is too costly to do on a large number of DNA samples. While <a href="https://www.cancer.gov/about-nci/organization/ccg/blog/2019/low-coverage-seq">low-coverage sequencing</a> reduces costs by reading smaller segments of the genome, it may miss some important genetic variation. With our new technology, geneticists can get the best of both worlds: <a href="https://www.broadinstitute.org/blog/what-exome-sequencing">sequencing the exome in depth</a> maximizes the likelihood of pinpointing <a href="https://doi.org/10.1038/s41586-022-04556-w">specific genes</a> that play a role in mental illness, while <a href="https://doi.org/10.1016%2Fj.ajhg.2021.03.012">sequencing the whole genome less in depth</a> allows researchers to process large numbers of whole genomes more cost-effectively.</p>
<h2>Personalizing medicine</h2>
<p>Our hope is that this new technology will allow researchers to sequence large sample sizes from a diverse range of ancestries to capture the full breadth of genetic variation. With a better understanding of the genetics of mental illness, clinicians and researchers will be better equipped to develop new treatments that work for everyone. </p>
<p>Genomic sequencing opened a new era of <a href="https://doi.org/10.1377%2Fhlthaff.2017.1624">personalized medicine</a>, which promises to deliver treatments tailored to each individual person. This can be done only if the genetic variations of all ancestries are represented in the data sets that researchers use to make new discoveries about disease and develop treatments.</p><img src="https://counter.theconversation.com/content/185997/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hailiang Huang receives funding from the National Institutes of Health and the Brain & Behavior Research Foundation. He is a member of the board of directors with the International Society of Psychiatric Genetics.</span></em></p>Existing genetic data and sequencing tools are overwhelmingly based on people of European ancestry, which excludes much of the rich genetic variation of the world.Hailiang Huang, Assistant Professor of Medicine, Harvard UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1227642019-09-03T13:40:36Z2019-09-03T13:40:36ZStop calling it a choice: Biological factors drive homosexuality<figure><img src="https://images.theconversation.com/files/290563/original/file-20190902-175705-15kuqu2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Biological factors shape sexual preference.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/lgbt-lesbian-couple-moments-happiness-concept-575079754?src=-1-53">Rawpixel.com/SHutterstock.com</a></span></figcaption></figure><p><a href="https://doi.org/10.1126/science.aat7693">Across cultures, 2% to 10% of people report having same-sex relations</a>. In the U.S., <a href="https://www.statista.com/topics/1249/homosexuality/">1% to 2.2% of women and men</a>, respectively, identify as gay. Despite these numbers, <a href="https://www.pewresearch.org/global/2013/06/04/the-global-divide-on-homosexuality/">many people still consider homosexual behavior to be an anomalous choice</a>. However, biologists have <a href="https://us.macmillan.com/books/9780312253776">documented homosexual behavior in more than 450 species</a>, arguing that same-sex behavior is not an unnatural choice, and may in fact play a vital role within populations.</p>
<p>In <a href="https://doi.org/10.1126/science.aat7693">a 2019 issue of Science magazine</a>, geneticist Andrea Ganna at the Broad Institute of MIT and Harvard, and colleagues, described the largest survey to date for genes associated with same-sex behavior. By analyzing the DNA of nearly half a million people from the U.S. and the U.K., they concluded that genes account for between 8% and 25% of same-sex behavior. </p>
<p><a href="https://www.nature.com/news/sex-redefined-1.16943">Numerous studies have established that sex is not just male or female</a>. Rather, it is a continuum that emerges from a person’s genetic makeup. Nonetheless, misconceptions persist that same-sex attraction is a choice that warrants condemnation or <a href="https://www.apa.org/pi/lgbt/resources/just-the-facts">conversion</a>, and leads to discrimination and persecution.</p>
<p><a href="https://wjsulliv.wixsite.com/sullivanlab">I am a molecular biologist</a> and am interested in this new study as it further illuminates the genetic contribution to human behavior. As the author of the book, <a href="https://www.penguinrandomhouse.com/books/608709/pleased-to-meet-me-by-bill-sullivan/9781426220555/">“Pleased to Meet Me: Genes, Germs, and the Curious Forces That Make Us Who We Are,”</a> I have done extensive research into the biological forces that conspire to shape human personality and behavior, including the factors influencing sexual attraction.</p>
<h2>The hunt for ‘gay genes’</h2>
<p>The new finding is consistent with multiple earlier studies of twins that indicated same-sex attraction is a heritable trait.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1200&fit=crop&dpr=1 600w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1200&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1200&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1508&fit=crop&dpr=1 754w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1508&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1508&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">A new study suggests that genes are responsible for between 8% and 25% of same-sex preference.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/dna-multi-color-isolated-on-white-717211195?src=-1-47">Guru 3D</a></span>
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<p>The 2019 study is the latest in a hunt for “gay genes” that began in 1993, when Dean Hamer <a href="https://doi.org/10.1126/science.8332896">linked male homosexuality to a section of the X chromosome</a>. As the ease and affordability of genome sequencing increased, additional gene candidates have emerged with potential links to homosexual behavior. So-called <a href="https://doi.org/10.1038/s41598-017-15736-4">genome-wide association studies identified a gene called <em>SLITRK6</em></a>, which is active in a brain region called the diencephalon that differs in size between people who are homosexual or heterosexual.</p>
<p>Genetic studies in mice have uncovered additional gene candidates that could influence sexual preference. A 2010 study <a href="https://doi.org/10.1186/1471-2156-11-62">linked sexual preference to a gene called fucose mutarotase</a>. When the gene was deleted in female mice, they were attracted to female odors and preferred to mount females rather than males. </p>
<p>Other studies have shown that <a href="https://doi.org/10.1038/nature06089">disruption of a gene called <em>TRPC2</em></a> can cause female mice to act like males. <a href="https://doi.org/10.1126/science.1069259">Male mice lacking <em>TRPC2</em></a> no longer display male-male aggression, and they initiate sexual behaviors toward both males and females. Expressed in the brain, <em>TRPC2</em> functions in the recognition of pheromones, chemicals that are released by one member of a species to elicit a response in another.</p>
<p>With multiple gene candidates being linked to homosexuality, it seemed highly unlikely that a single “gay” gene exists. This idea is further supported by <a href="https://doi.org/10.1126/science.aat7693">the new study</a>, which identified five new genetic loci (fixed positions on chromosomes) correlating with same-sex activity: two that appeared in men and women, two only in men, and one only in women.</p>
<h2>How might these genes influence same-sex behavior?</h2>
<p>I find it intriguing that some of the genes from men identified in Ganna’s study are associated with olfactory systems, a finding that has parallels to the work in mice. Ganna’s group found other gene variants that may be linked with sex hormone regulation, which other scientists have previously suggested plays a large role in shaping the brain in ways that influence sexual behavior. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=846&fit=crop&dpr=1 600w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=846&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=846&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1063&fit=crop&dpr=1 754w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1063&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1063&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Conditions in the uterus during pregnancy are thought to influence the sexual preferences of the child.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/beautiful-pregnant-woman-shopping-bags-outdoors-503149633?src=-1-18">Anna Om/Shutterstock.com</a></span>
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<p>Males with a genetic condition called <a href="https://ghr.nlm.nih.gov/condition/androgen-insensitivity-syndrome">androgen insensitivity syndrome</a> can develop female genitalia and are usually brought up as girls, despite being genetically male – with an X and Y chromosome – and they are attracted to men. This suggests that testosterone is needed to “masculinize” a prenatal brain; if that doesn’t happen, the child will grow up to desire men. </p>
<p>Similarly, girls who have a genetic condition called <a href="https://www.nichd.nih.gov/health/topics/cah">congenital adrenal hyperplasia</a> are exposed to unusually high levels of male hormones like testosterone while in the womb, which may masculinize their brain and increase the odds of lesbianism. </p>
<p>It’s also possible that hormonal shifts during pregnancy could affect how a fetus’ brain is configured. In rats, <a href="https://doi.org/10.1210/en.2011-0277">manipulation of hormones during pregnancy</a> produces offspring that exhibit homosexual behavior.</p>
<h2>Why does homosexual behavior exist?</h2>
<p>Several hypotheses have been advanced to explain how homosexuality can be beneficial in perpetuating familial genes. One idea involves the concept of kin selection, whereby people work to ensure the passage of their family’s genes into subsequent generations. Gay uncles and aunts, for example, are “<a href="https://doi.org/10.1177/0956797609359623">helpers in the nest</a>” that help raise other family members’ children to nurture the family tree.</p>
<p>Another idea suggests that homosexuality is a “trade-off trait.” For example, certain genes in women help increase their fertility, but <a href="https://doi.org/10.1111/j.1743-6109.2008.00944.x">if these genes are expressed in a male</a>, they predispose him toward homosexuality.</p>
<p>Sexual behavior is widely diverse and governed by sophisticated mechanisms throughout the animal kingdom. As with other complex behaviors, it is not possible to predict sexuality by gazing into a DNA sequence as if it were a crystal ball. Such behaviors emerge from constellations of hundreds, perhaps thousands, of genes, and how they are regulated by the environment.</p>
<p>While there is no single “gay gene,” there is overwhelming evidence of a biological basis for sexual orientation that is programmed into the brain before birth based on a mix of genetics and prenatal conditions, none of which the fetus chooses.</p>
<p>[ <em>You’re smart and curious about the world. So are The Conversation’s authors and editors.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=youresmart">You can read us daily by subscribing to our newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/122764/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Bill Sullivan does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>A new study of nearly 500,000 individuals finds that many genes affect same-sex behavior, including newly identified candidates that may regulate smell and sex hormones.Bill Sullivan, Professor of Pharmacology & Toxicology, Indiana University School of MedicineLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1025202018-09-04T09:09:35Z2018-09-04T09:09:35ZGenes shown to influence how well children do throughout their time at school<figure><img src="https://images.theconversation.com/files/234631/original/file-20180903-41720-14jmscn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/home">Shutterstock.</a></span></figcaption></figure><p>Children differ widely in how well they do at school. In recent years, researchers have shown that around two-thirds of differences in school achievement <a href="http://journals.sagepub.com/doi/full/10.1177/0956797613486982">can be explained</a> by differences in children’s genes. </p>
<p>Genes have been shown to influence how well children do at <a href="https://europepmc.org/articles/pmc2784897">primary school</a>, at the end of <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080341">compulsory education</a>, and even <a href="https://theconversation.com/the-same-genes-influence-exam-results-across-a-range-of-school-subjects-45059">in different subjects</a>. However, less is known about how genetic and environmental factors contribute to how well a child continues to do academically throughout their time at school. </p>
<p>To study this, we used a sample of over 6,000 pairs of twins who are part of the UK-representative <a href="https://www.teds.ac.uk/about-teds">Twins Early Development Study</a> and analysed their test scores from primary school to the end of compulsory education. Our new <a href="https://www.nature.com/articles/s41539-018-0030-0">research found</a> that the twins’ educational achievement was remarkably stable: children who do well in primary school also tend to perform well in GCSE exams, taken at the end of compulsory education. </p>
<p>Using twins allows us to estimate the proportion of differences that can be explained by genetic factors. Identical twins share 100% of their genes, while non-identical twins share on average 50% of the genes that differ between people, just like other siblings. If identical twins are more alike on a particular trait than non-identical twins, such as school achievement, we can infer that it is influenced by their genes. We can then estimate the heritability of that trait – or the proportion of differences that are down to the differences in children’s DNA sequence. </p>
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Read more:
<a href="https://theconversation.com/the-same-genes-influence-exam-results-across-a-range-of-school-subjects-45059">The same genes influence exam results across a range of school subjects</a>
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<p>We looked at what factors influenced stability in educational achievement – when grades in a standardised test remain similar between primary and secondary school. We found that about 70% of the stability in achievement is explained by genetic factors, while 25% is accounted for by the twins’ shared environment, such as growing up in the same family and attending the same school. The remaining 5% was explained by their non-shared environment, such as different friends or different teachers. </p>
<p>When there was a change in educational achievement – where grades increased or dropped between primary and secondary school – we found this was largely explained by those environmental factors that are not shared by twins. </p>
<p>It’s reasonable to assume that this substantial influence of genes on the continuity of children’s achievement during their time at school can be explained by intelligence. Yet we found the influence of genes remained substantial – at 60% – even after accounting for intelligence, which was measured using several verbal and nonverbal tests taken by the twins over the course of childhood and adolescence.</p>
<h2>Predicting achievement using DNA</h2>
<p>While twin study estimates such as this can tell us about traits within large groups of people, recent scientific advances are revealing more about the influence of genes on the individual. There has been considerable recent success in identifying genetic variants associated with <a href="https://www.nature.com/articles/nature17671">educational attainment</a> through what are called genome-wide association studies (GWAS). These studies pinpoint genetic markers associated with certain traits. However, each genetic marker explains a very small proportion (less than 0.1%) of the individual differences in school performance. </p>
<p>A more powerful method was recently developed that sums up thousands of the genetic markers found in the GWAS studies to instead calculate a genome-wide “polygenic score”. This score <a href="https://www.nature.com/articles/s41588-018-0147-3">is now being used</a>, with increasing levels of accuracy, to predict variance in a trait, such as school achievement, for people unrelated to each other. </p>
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Read more:
<a href="https://theconversation.com/your-genes-can-help-predict-how-well-youll-do-in-school-heres-how-we-cracked-it-62848">Your genes can help predict how well you'll do in school – here's how we cracked it</a>
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<p>As part of our new study, we used data from <a href="https://www.nature.com/articles/nature17671">previous GWAS analyses</a> to create a polygenic score for education attainment. We calculated a score for one of each pair of our 6,000 sets of twins (so that everybody in this part of the study was unrelated). This predicted whether they would do well across their time at school. These predictions ranged from accounting for 4% of the variance in educational attainment at the start of primary school, to 10% of the variance at GCSE levels. Our findings confirmed the results from the first part of our twins analysis – that the same genetic variants play a role in explaining why children differ in achievement at every stage in development.</p>
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<p><em><strong>To hear more about Twins studies and why they are so important for science, listen to the <a href="https://theconversation.com/anthill-26-twins-98271">Twins episode</a> of The Anthill podcast.</strong></em> </p>
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<p>Our findings, which suggest that genes influence how well a child will do across the length of their time at school, should provide additional motivation to identify children in need of interventions as early as possible, as problems are likely to remain throughout the school years. In the future, polygenic score prediction, together with the prediction of environmental risks – such as exposure to certain neighbourhood, family, and school characteristics – might provide a tool to identify children with educational problems very early in life. They could then be provided with individualised learning programmes. </p>
<p>For example, we could use DNA tests at birth to identify children at genetic risk for developing reading problems, and give them early intervention. As preventive interventions have greater chances of succeeding early in life, a great strength of polygenic scores is that they can predict at birth just as well as later in life, which could be of particular help for those children who are likely to struggle the most.</p><img src="https://counter.theconversation.com/content/102520/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>New research is pinpointing how much genes influence the stability of educational achievement.Kaili Rimfeld, Postdoctoral Research Associate, King's College LondonMargherita Malanchini, Postdoctoral Fellow, The University of Texas at AustinLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/976712018-06-08T10:53:32Z2018-06-08T10:53:32ZNeurons made from blood cells – a new tool for understanding brain diseases<figure><img src="https://images.theconversation.com/files/222074/original/file-20180606-137322-cyv5g6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Marius Wernig, Thomas C. Südhof and their colleagues created these “Induced neuronal (iN) cells” from adult human blood cells. </span> <span class="attribution"><span class="source">Marius Wernig</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p><a href="http://stemcellphd.stanford.edu/faculty/marius-wernig.html">Our team at Stanford University</a> has just figured out the recipe for converting blood cells from adults directly into nerve cells, or neurons. </p>
<p>You may be wondering why anyone would want to convert blood into brain cells. Researchers like myself would like to gain a better understanding of what causes brain diseases such as autism, schizophrenia or major depression. But it is difficult to study complex diseases like these in the lab. </p>
<p><a href="http://doi.org/10.1073/pnas.1720273115">Our new procedure</a> should make this research easier because we can collect blood cells from a patient with schizophrenia, for example, and see whether disease processes that happens in an individual’s brain can be replicated in blood-derived neurons in the petri dish. This research will not only provide insights into how diseases develop but will also create a way to test new therapies before they are given to patients. </p>
<h2>Why are neuropsychiatric diseases so difficult to study?</h2>
<p>What makes brain diseases hard to study is that every person has a unique genetic makeup which means that the same disease – autism or schizophrenia or depression – manifests differently in every individual. In addition, only a small percentage of patients have mutations in a single gene that appears to be responsible for the disease. </p>
<p>When the <a href="https://doi.org/10.1038/mp.2012.21">DNA of hundreds of patients</a> with <a href="http://doi.org/10.1038/ng.2742">neuropsychiatric diseases</a> and healthy individuals was screened for disease-causing genes, certain versions of genes were more common in <a href="http://doi.org/10.1038/ng.3529">patients versus the healthy population</a>, suggesting they may play a role in causing the disease. </p>
<p>This suggests that the majority of patients carry multiple genes that all contribute to their condition. The contribution of each gene is small, but the combination of dozens of genetic variations add up to a severe disease. </p>
<p>For this reason, it is challenging to assess the role of these minor genes in the whole disease process, figure out which ones are key players and determine the critical combination of genetic variations necessary to trigger disease. Because we don’t know the key genes involved, we cannot engineer mice that accurately mimic the disease process in humans, and we can’t test therapies to address these illnesses.</p>
<h2>Reprogramming the cell</h2>
<p>Cellular reprogramming, the ability to convert one cell type into another, offers a possible solution to this problem. In 2006, scientists showed that skin cells could be transformed into <a href="http://doi.org/10.1016/j.cell.2006.07.024">pluripotent stem cells</a> – cells that have the potential to develop into many cell types – which in turn could be coaxed into neurons. A few years later, in 2010, we simplified this two-step process and discovered a way to convert <a href="http://doi.org/10.1038/nature08797">skin cells directly into neurons</a>.</p>
<p>But obtaining skin cells is not straightforward and involves a painful procedure. Moreover, the skin cells have to be grown before they are converted into other cells, which can introduce artificial mutations not relevant to causing the disease.</p>
<p>With <a href="https://doi.org/10.1073/pnas.1720273115">our approach</a>, we can take just a few drops of blood and generate tens of thousands of neurons. </p>
<p>We can complete this shape-shifting transformation of one cell type into another by adding just four specific proteins – which we determined play vital roles in brain development – to freshly drawn or stored blood cells. These four factors are enough to rapidly reprogram these cells and transform them into neurons within a few weeks of treatment. </p>
<p>Over this period the white blood cells change shape, from a ball-shaped cell to a neuron with delicate tentacle-like branches. They display proteins that typically decorate the surface of neurons, and in our experiments they behaved like neurons and transmitted electrical signals. Compared to neurons in the brain the “induced” neurons appear less mature. Our technique is already useful for some applications, for others that require mature neurons it still needs to be refined. </p>
<p>Our strategy allows scientists to generate neurons from patients affected with a disease of interest which harbor all the genetic elements that actually cause the condition. We will still need to create neurons from many patients and healthy subjects and analyze the genes that are active in each group before we can determine which genes are involved in all forms of the disease. Through this method, we will be hopefully be able to identify the most relevant genes which should be good targets for disease-modifying medicines. </p>
<p><em>Tom Südhof, professor of molecular and cellular physiology at Stanford University, also contributed to this article and owns shares of Neucyte, Inc.</em></p><img src="https://counter.theconversation.com/content/97671/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marius Wernig owns shares of Neucyte, Inc. He also owns shares and consults for Fulcrum Therapeutics. This work was funded by Stanford University's internal grants.</span></em></p>Figuring out what causes diseases like autism, schizophrenia and depression is tricky. Now Stanford University researchers are turning blood into brain cells to study these diseases in a dish.Marius Wernig, Associate Professor of Pathology at the Institute for Stem Cell Biology and Regenerative Medicine, Stanford UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/621222016-07-07T18:05:40Z2016-07-07T18:05:40ZNew study may help explain how type 2 diabetes and obesity are inherited<figure><img src="https://images.theconversation.com/files/129584/original/image-20160706-12736-1k0sal.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/cat.mhtml?lang=en&language=en&ref_site=photo&search_source=search_form&version=llv1&anyorall=all&safesearch=1&use_local_boost=1&autocomplete_id=&search_tracking_id=6eUwKu6tlBhJ5n58ij3Asg&searchterm=DNA&show_color_wheel=1&orient=&commercial_ok=&media_type=images&search_cat=&searchtermx=&photographer_name=&people_gender=&people_age=&people_ethnicity=&people_number=&color=&page=1&inline=328604552">Sergey Nivens/Shutterstock.com</a></span></figcaption></figure><p>The most exciting recent development in human genetics research has been the ability to perform large-scale systematic studies of genetic variation in thousands of people. These genome-wide association studies (GWASs) have revolutionised our understanding of many different complex diseases. </p>
<p>But despite these advances, we are still only able to explain a small fraction of the heritability of many health conditions. In a study that my lab has <a href="http://science.sciencemag.org/content/early/2016/07/06/science.aaf7040">just published in Science</a>, we show that a person’s attributes could be strongly influenced by genetic variation in an unexpected part of the genome that has been overlooked in previous studies.</p>
<p>The environmental factors that play a role alongside genetics in determining a person’s attributes are also present in the womb. When offspring are in the womb, what their mothers experience environmentally (including diet, stress, smoking) has the potential to influence an offspring’s attributes when they become adults. This “developmental programming” is understood to be a large contributor to the obesity epidemic seen today.</p>
<p>A key player in this process is epigenetics. Epigenetics are modifications that sit outside the genome and determine which bits of DNA to make more active or inactive. One such modification involves tagging DNA with compounds called methyl groups. Methyl groups determine whether genes are expressed (switched on) or not. Liver cells and kidney cells are genetically identical apart from their epigenetic marks. It has been proposed that in response to a poor environment in the womb, an offspring’s epigenetic profile will change.</p>
<p>In our study, we compared the offspring of pregnant mice when given a low-protein diet (8% protein) and a normal diet (20% protein). After they were weaned, all offspring were given a normal diet. We then looked at the difference in the offspring’s DNA methylation, comparing those mice whose mothers had a low-protein diet to those whose mothers had a normal diet.</p>
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<img alt="" src="https://images.theconversation.com/files/129582/original/image-20160706-12736-yhc5nj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/129582/original/image-20160706-12736-yhc5nj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/129582/original/image-20160706-12736-yhc5nj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/129582/original/image-20160706-12736-yhc5nj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/129582/original/image-20160706-12736-yhc5nj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/129582/original/image-20160706-12736-yhc5nj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/129582/original/image-20160706-12736-yhc5nj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Some of the pregnant mice were fed a low-protein diet.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/cat.mhtml?lang=en&language=en&ref_site=photo&search_source=search_form&version=llv1&anyorall=all&safesearch=1&use_local_boost=1&autocomplete_id=&search_tracking_id=gzEnLoge2vho_LZjCCTozg&searchterm=mouse%20model&show_color_wheel=1&orient=&commercial_ok=&media_type=images&search_cat=&searchtermx=&photographer_name=&people_gender=&people_age=&people_ethnicity=&people_number=&color=&page=1&inline=177481676">Marques/Shutterstock.com</a></span>
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<h2>Looking in the wrong place</h2>
<p>Initially, we found nothing, so that was a big surprise, but then we looked at the ribosomal DNA (rDNA) data and found huge epigenetic differences. Ribosomal DNA is the genetic material that forms ribosomes – the protein-building machines within the cell.</p>
<p>When cells are stressed – for example when nutrient levels are low – they alter protein production as a survival strategy. In the mice whose mothers were fed a low-protein diet, we found that they had methylated rDNA. This slowed the expression of their rDNA and resulted in smaller offspring – as much as 25% lighter.</p>
<p>These epigenetic effects occur in a critical developmental window while the offspring is in the womb but is a permanent effect that remains into adulthood. So a mother’s low-protein diet while pregnant is likely to have more severe consequence on the offspring’s epigenetic state and weight than an offspring’s own diet after it has been weaned.</p>
<p>Looking beyond the epigenetic markers, when we looked at the basic genetic sequence of the rDNA, we found an even bigger surprise. Even though all the mice in the study were bred to be genetically identical, we found that the rDNA between the individual mice was not genetically identical – and that, even within an individual mouse, different copies of rDNA were genetically distinct. So there is huge variation in rDNA which is also playing a big role in determining the attributes of offspring.</p>
<p>In any given genome, there are many copies of rDNA, and we found that not all copies of the rDNA were responding the same way epigenetically. Only one type of rDNA – the “A-variant” – appeared to undergo methylation and affect weight. This means that the epigenetic response of a given mouse is determined by the genetic variation of their rDNA – those who have more A-variant rDNA end up being smaller. </p>
<p>Heritability (how much the risk of a disease is explained by genetic factors) of type 2 diabetes has been estimated to be between 25% and 80% in different studies. However, only about 20% of the heritability of type 2 diabetes has been explained by genome studies of people with the disease. </p>
<p>The fact that genetic variation of ribosomal DNA seems to have such a strong influence suggests that GWASs in humans could be missing a key part of the puzzle, as so far they have only looked at the single copy part of people’s genomes. Genetic and epigenetic analysis of rDNA in humans could yield very important insights into a variety of human diseases.</p><img src="https://counter.theconversation.com/content/62122/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span><a href="mailto:v.rakyan@qmul.ac.uk">v.rakyan@qmul.ac.uk</a> receives funding from BBSRC.</span></em></p>Scientists find the missing link in epigenetics that could explain the mystery of inherited disease.Vardhman Rakyan, Professor of Epigenetics, Queen Mary University of LondonLicensed as Creative Commons – attribution, no derivatives.