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</li> <li class="tag__item"> <a class="tag__link" href="/neuro/topic.aspx?id=1017">Psychiatry</a> </li> <li class="tag__item"> <a class="tag__link" href="/neuro/topic.aspx?id=1023">Schizophrenia</a> </li> </ul> </div> <h1 class="content-header__heading" itemprop="name">Sex-specific Genetic Effects Across Neuropsychiatric and Behavioral Traits Identified for the First Time</h1> <div class="content-header__metadata"> <p class="content-metadata"> <span class="content-metadata__media -journal">Journal</span> <time class="date" datetime="2021-12-17" itemprop="datePublished">Published on December 17, 2021 </time> </p> <p data-module="share-links"> </p> <p class="citation"> Originally published on <cite itemprop="citation"><a href="https://www.biologicalpsychiatryjournal.com/article/S0006-3223(21)00033-0/fulltext">Biological Psychiatry</a></cite> </p> </div> </div> </header> <div class="-padding--vertical -padding--horizontal"> <div class="layout-columns -width--wide -centered"> <div class="layout-columns__main"> <div class="layout-columns__main__content"> <div class="content-summary"> <h3 class="content-summary__heading">Key findings</h3> <ul> <li>This study evaluated sex differences within and across 20 neuropsychiatric and behavioral traits using three complementary approaches—estimation of single nucleotide polymorphism (SNP)–based heritability, genetic correlation and heterogeneity analyses</li> <li>SNP-based heritability differed significantly by sex for recurrent major depressive disorder, autism spectrum disorder and schizophrenia; these traits were among those with the largest sample sizes</li> <li>There were moderate-to-high genetic correlations between males and females for nearly all traits</li> <li>There were no significant sex differences in the genetic effects of any individual SNP, but the number of children born was associated with GLB1L2, risk-taking behavior was associated with HFE2 and AGO2, and schizophrenia was associated with SLTM</li> <li>A number of pairs of traits were found to share sex-dependent genetic effects; for example, there were correlations between autism spectrum disorder and attention-deficit hyperactivity disorder and between bipolar disorder and schizophrenia</li> </ul> </div> <p>It's now established that neuropsychiatric and behavioral disorders share a considerable portion of their genetic "architecture" with each other, and the prevalence and presentation of many disorders differ by sex.</p><div class="article__signup-container"> <div class="email-signup-inline__container -background--white"> <style> #email-signup-inline { /* 540px */ background-image: url(/assets/raw/email-signup/cardiovascular-sub-callout.jpg); } @media only screen and (-webkit-min-device-pixel-ratio: 2), only screen and (min--moz-device-pixel-ratio: 2), only screen and (-moz-min-device-pixel-ratio: 2), only screen and (-o-min-device-pixel-ratio: 2/1), only screen and (min-device-pixel-ratio: 2), only screen and (min-resolution: 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<input type="hidden" id="tfa_10" name="tfa_10" value="Sub_Psych" class=""><input type="hidden" id="tfa_12" name="tfa_12" value="AiM Sub Box" class=""> </div> <div style="clear:both"></div> <input type="hidden" value="531" name="tfa_dbFormId" id="tfa_dbFormId"> <input type="hidden" value="" name="tfa_dbResponseId" id="tfa_dbResponseId"> <input type="hidden" value="05d7e041608a6e49abd40266b2379304" name="tfa_dbControl" id="tfa_dbControl"> <input type="hidden" value="" name="tfa_dbWorkflowSessionUuid" id="tfa_dbWorkflowSessionUuid"> <input type="hidden" value="4" name="tfa_dbVersionId" id="tfa_dbVersionId"> <input type="hidden" value="" name="tfa_switchedoff" id="tfa_switchedoff"> </form> </div> </div> </div> <script id="open-telemetry-script" type="text/javascript" src="https://massgeneral.tfaforms.net/dist/open-telemetry/open-telemetry.152f594b0ae29ae89d4a.js" data-customer-id="1118" data-exporter-url="https://us-east-1-otel.formassembly.com/v1/traces" data-exporter-console="0" ></script> <script src="https://massgeneral.tfaforms.net/api_v2/sst/copy-and-paste"></script> </div> </div> </div> <p>Given this evidence, the international Psychiatric Genomics Consortium formed a Sex Differences Cross-Disorder Analysis Group to investigate whether the genetic correlations of neuropsychiatric and behavioral traits are different for males and females. <a href="https://advances.massgeneral.org/contributors/contributor.aspx?id=1699" target="_blank" rel="noopener noreferrer">Jill M. Goldstein, PhD, MPH</a>, executive director of the <a href="https://www.icon.mgh.harvard.edu/" target="_blank" rel="noopener noreferrer">Innovation Center on Sex Differences in Medicine</a> and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women's Health, and <a href="https://advances.massgeneral.org/contributors/contributor.aspx?id=1133" target="_blank" rel="noopener noreferrer">Jordan W. Smoller, MD, ScD</a>, director of the <a href="https://www.massgeneral.org/psychiatry/research/researchlab.aspx?id=1747" target="_blank" rel="noopener noreferrer">Psychiatric and Neurodevelopmental Genetics Unit</a> in the <a href="https://www.massgeneral.org/psychiatry" target="_blank" rel="noopener noreferrer">Department of Psychiatry</a> at Massachusetts General Hospital, are two senior members of the group.</p> <p>In <a href="https://www.biologicalpsychiatryjournal.com/article/S0006-3223%2821%2900033-0/fulltext" target="_blank" rel="noopener noreferrer"><em>Biological Psychiatry</em></a><em>,</em> the group reports that the majority of genetic effects they identified for neuropsychiatric and behavioral traits were similar for men and women, but some were sex-differentiated. Moreover, the group shows for the first time that a portion of sex-differentiated genetic effects are shared across traits.</p> <h2>SNP-based Heritability</h2> <p>The researchers analyzed sex-stratified data on 20 neuropsychiatric and behavioral traits from European-ancestry genome-wide association studies. They calculated that single nucleotide polymorphism (SNP)-based heritability differed significantly by sex for recurrent major depressive disorder (MDDR), autism spectrum disorder (ASD) and schizophrenia. These traits were among those with the largest sample sizes.</p> <p>For several traits, sex differences could not be assessed because of insufficient power or excessive heterogeneity: post-traumatic stress disorder and MDDR in males and ASD and alcohol dependence in females.</p> <h2>Between-Sex, Within-Trait Genetic Correlations</h2> <p>There were moderate-to-high genetic correlations between males and females for nearly all traits that could be studied. As exceptions, there was a modest degree of heterogeneity between males and females for risk-taking behavior and educational attainment.</p> <h2>Between-Sex, Within-Trait Heterogeneity</h2> <p>No sex differences in the genetic effects of any individual SNP were statistically significant at the genome-wide level. However, several traits had significant sex-differentiated gene associations: the number of children born was associated with <em>GLB1L2,</em> risk-taking behavior was associated with <em>HFE2</em> and <em>AGO2,</em> and schizophrenia was associated with <em>SLTM.</em></p> <h2>Shared Sex-Differentiated Effects</h2> <p>In some cases, a sex difference observed at a gene was shared by a pair of traits. For example, there were correlations between ASD and attention-deficit hyperactivity disorder and between bipolar disorder and schizophrenia. All correlations were small or moderate but statistically significant.</p> <p>Using and extending the same cohort, reported in <a href="https://advances.massgeneral.org/neuro/journal.aspx?id=2085" target="_blank" rel="noopener noreferrer"><em>Biological Psychiatry</em></a>, Dr. Goldstein and Dr. Smoller found significant sex differences shared and non-shared in the genetic architecture of psychiatric disorders themselves, that is, schizophrenia, bipolar disorder, and major depressive disorder. While there was substantial genetic overlap in these disorders between men and women, there were significant sex-dependent differences in how genes related to the central nervous system, immune system, and vasculature.</p> <h2>Research Implications</h2> <p>Sex differences in the common autosomal genetic architecture of the traits studied here were small and polygenic, and thus contribute one piece of the puzzle in understanding the pronounced sex differences in the prevalence of many psychiatric disorders. Larger samples are needed to detect interaction effects with sex at the individual SNP level for traits, as was conducted for psychiatric disorders in the previous work cited above.</p> <p>Sex differences in the prevalence of many psychiatric disorders are likely explained by the interplay between genes and environment and may be trait-specific across disorders. Considerably more research is needed to understand these relationships, which is critical for accelerating the development of sex-specific diagnostics and therapeutics.</p><p class="fat-link__wrapper u-text-right"> <a class="fat-link -caret -large" href="https://www.biologicalpsychiatryjournal.com/article/S0006-3223(21)00033-0/fulltext">view original journal article <em>Subscription may be required</em></a> </p> <div class="article-attribution" itemscope itemtype="http://schema.org/ScholarlyArticle"> <p class="article-attribution__logo" itemscope itemtype="http://schema.org/Periodical"> <a href="https://www.biologicalpsychiatryjournal.com/article/S0006-3223(21)00033-0/fulltext"> <span class="a11y-sr-only" itemprop="name">Biological Psychiatry</span> </a> </p> <p class="article-attribution__metadata" itemscope itemtype="http://schema.org/PublicationIssue"> <span> Journal Article Published: <time datetime="2021-01-08" itemprop="datePublished">January 8, 2021</time> </span> </p> </div> <p class="cta">Learn more about the <a href="https://www.massgeneral.org/psychiatry/research/psychiatric-and-neurodevelopmental-genetics-unit/">Psychiatric and Neurodevelopmental Genetics Unit</a></p> <p class="cta">Learn more about <a href="https://www.massgeneral.org/psychiatry/research/">research in the Department of Psychiatry</a></p> </div> </div> <aside class="layout-columns__sidebar -article__contributors"> <div class="layout-columns__sidebar__content"> <div class="profile-compact__wrapper"> <p class="u-no-margin"> <strong>Contributors</strong> </p> <div class="profile -compact" itemscope itemtype="http://schema.org/Person"> <div class="profile__content"> <h3 class="profile__name" itemprop="name"> <a href="/contributors/contributor.aspx?id=1699" itemprop="url">Jill M. Goldstein, PhD ›</a></h3><p class="profile__title" itemprop="jobTitle">Founder & Executive Director, Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Helen T. Moerschner Endowed MGH Research Institute Chair in Women’s Health, Professor of Psychiatry & Medicine, Harvard Medical School</p> </div> <p class="profile__image"> <img alt="Dr. Jill Goldstein" itemprop="image" srcset="/assets/images/contributors/jill_goldstein_advances.png, /assets/images/contributors/jill_goldstein_advances_2x.png 2x" src="/assets/images/contributors/jill_goldstein_advances.png"> </p> </div> <div class="profile -compact" itemscope itemtype="http://schema.org/Person"> <div class="profile__content"> <h3 class="profile__name" itemprop="name"> <a href="/contributors/contributor.aspx?id=1133" itemprop="url">Jordan W. Smoller, MD, ScD ›</a></h3><p class="profile__title" itemprop="jobTitle">Associate Chief for Research, Department of Psychiatry, Massachusetts General Hospital, Director, Psychiatric and Neurodevelopmental Genetics Unit, Professor of Psychiatry at Harvard Medical School and Professor in the Department of Epidemiology at the Harvard School of Public Health</p> </div> <p class="profile__image"> <img alt="" itemprop="image" srcset="/assets/images/contributors/Jordan_Smoller_advances.png, /assets/images/contributors/Jordan_Smoller_advances_2x.png 2x" src="/assets/images/contributors/Jordan_Smoller_advances.png"> </p> </div> </div> </div> </aside> <section class="topics-layout -article__related"> <div class="topics-layout__inner"> <div class="topics-layout__sidebar"> <h2 class="section-heading">Related topics</h2> </div> <div class="topics-layout__main"> <ul class="topics-list" data-module="topics-list"> <li><a href="/neuro/topic.aspx?id=1031">Depression</a></li> <li><a href="/neuro/topic.aspx?id=1017">Psychiatry</a></li> <li><a href="/neuro/topic.aspx?id=1023">Schizophrenia</a></li> </ul> </div> </div> </section> <section class="-padding--horizontal -padding--vertical -article__related"> <div class="layout-columns -width--wide -centered"> <div class="layout-columns__pod--half"> <div class="content-tease" itemscope itemtype="http://schema.org/ScholarlyArticle"> <p class="content-tease__topic"> <span class="highlight">Related</span> </p> <h3 class="content-tease__heading" itemprop="name"> <a href="/neuro/journal.aspx?id=2091" itemprop="url">Prenatal Exposure to Proinflammatory Cytokines May Increase Risk of Psychiatric Disorders by Sex 45 years later in Adulthood</a> </h3> <p itemprop="description"> <p>Jill M. Goldstein, PhD, of the Department of Psychiatry, and colleagues determined that middle-aged individuals exposed in utero to pro-inflammatory cytokines exhibit dysregulation of stress response brain circuitry, which has been implicated in psychiatric disorders and many other chronic disorders.</p></p> <p class="content-tease__related"> <a href="/neuro/specialty.aspx?id=1004" itemprop="relatedLink">Neuroscience</a>, <a href="/obgyn/specialty.aspx?id=1006" itemprop="relatedLink">OB/GYN</a>, <a href="/neuro/topic.aspx?id=1017" itemprop="relatedLink">Psychiatry</a> </p> <p class="content-metadata"> <span class="content-metadata__media -journal">Journal</span> <time class="date" datetime="2021-11-22" itemprop="datePublished">November 22, 2021</time> </p> </div> </div> <div class="layout-columns__pod--half"> <div class="content-tease" itemscope itemtype="http://schema.org/ScholarlyArticle"> <p class="content-tease__topic"> <span class="highlight">Related</span> </p> <h3 class="content-tease__heading" itemprop="name"> <a href="/neuro/journal.aspx?id=2101" itemprop="url">COVID-19 May Cause a Distinct Type of Major Depression</a> </h3> <p itemprop="description"> <p>Roy H. Perlis, MD, MSc, of the Department of Psychiatry, and colleagues compared features of major depressive disorder in individuals with or without prior COVID-19. They found indirect evidence that symptoms are a sequela of COVID-19 pathophysiology in a subset of individuals.</p></p> <p class="content-tease__related"> <a href="/research-and-innovation/topic.aspx?id=1056" itemprop="relatedLink">COVID-19</a>, <a href="/neuro/topic.aspx?id=1031" itemprop="relatedLink">Depression</a>, <a href="/neuro/specialty.aspx?id=1004" itemprop="relatedLink">Neuroscience</a>, <a href="/neuro/topic.aspx?id=1017" itemprop="relatedLink">Psychiatry</a> </p> <p class="content-metadata"> <span class="content-metadata__media -journal">Journal</span> <time class="date" datetime="2021-12-07" itemprop="datePublished">December 7, 2021</time> </p> </div> </div> </div> </section> </div> </div> </article> </div> </main>  <footer class="site-footer"> <div class="-padding--horizontal"> <nav aria-label="Footer links" class="content-container -width--wide -centered -padding--bottom"> <ul class="footer__nav" role="presentation"> <li> <a 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