A global research project has mapped out the genetic basis of major depression

Results from the largest human study of its kind suggest that different psychiatric diseases share a number of the same genetic variants, some of which start to show heightened expression during pregnancy and may impact on neurodevelopment. The study, by researchers at Massachusetts General Hospital (MGH) and the Psychiatric Genomics Consortium, identified more than 100 genetic variants that were linked with at least two of eight psychiatric disorders, more than 20 loci that were linked with four or more disorders, as well as nearly three dozen loci that hadn’t previously been linked with any of the eight disorders.

“Understanding how specific genetic variations may contribute to a broad spectrum of illnesses can tell us something about the degree to which these disorders may have a shared biology,” said research lead Jordan W. Smoller, MD, ScD, director of MGH’s Psychiatric and Neurodevelopmental Genetics Unit and a professor of psychiatry at Harvard Medical School (HMS). “To the extent that these genes may have broad effects, they could be potential targets for developing new treatments that might benefit multiple conditions.” Smoller and colleagues report their findings in Cell, in a paper titled, “Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders.”

Psychiatric disorders affect more than 25% of the population in any given year, and are a major cause of disability worldwide, the authors stated. The results of research in twins, and from large-scale genomic studies suggest that genetic variation has a major influence on a broad range of psychiatric disorders. Many risk loci have already been identified through genome-wide association studies (GWAS) for disorders spanning schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), and attention-deficit/hyperactivity disorder (ADHD). Understanding how these variants impact on disease isn’t easy, as genes are often pleiotropic, meaning that they produce multiple effects in the body. And as the authors pointed out, “Psychiatric disorders are highly polygenic, with a large proportion of heritability contributed by common variation.”

Understanding the extent and biological significance of cross-disorder genetic influences will help with disease classification, as well as provide new insights for drug development and risk prediction, they suggested. “In addition, characterizing the functional genomics of cross-phenotype genetic effects may reveal fundamental properties of pleiotropic loci that differentiate them from disorder-specific loci and help identify targets for diagnostics and therapeutics.”

Previous research by the Psychiatric Genomics Consortium’s (PGC) Cross-Disorder Group had identified genetic loci with pleiotropic effects across five disorders, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, and major depression, in more than 33,000 cases and nearly 28,000 controls. For the newly reported study, the PGC and MGH teams analyzed genome-wide, single nucleotide polymorphism (SNP) data for an expanded sample of 232,964 cases and 494,162 controls, spanning the same five psychiatric disorders, and an additional three: anorexia nervosa, obsessive-compulsive disorder, and Tourette syndrome.

The analysis identified 146 lead SNPs that were associated with at least one disorder, including 35 novel loci. Of this total, 109 gene variants were found to affect the risk for more than one psychiatric disorder. As the team wrote, “… variant-level analyses support the existence of substantial pleiotropy, with nearly 75% of the 146 genome-wide significant SNPs influencing more than one of the eight disorders. We also identified a set of 23 loci with particularly extensive pleiotropic profiles, affecting four or more disorders.”

The researchers used the results to divide the eight disorders into three groups of genetically related conditions: those characterized by compulsive behaviors (anorexia nervosa, obsessive-compulsive disorder, and, to a lesser extent, Tourette syndrome); mood and psychotic disorders (bipolar disorder, major depression, and schizophrenia); and early-onset neurodevelopmental disorders (autism spectrum disorder, ADHD and Tourette syndrome). The researchers also found evidence that genes associated with multiple disorders show increased expression beginning in the second trimester of pregnancy and appeared to play an important role in brain development.

Interestingly, the team identified a set of loci that had opposite effects on the risk of different psychiatric disorders. “These results underscore the complexity of genetic relationships among related disorders and suggest that overall genetic correlations may obscure a more complex set of genetic relationships at the level of specific loci and pathways, as seen in immune-mediated diseases,” the scientists noted. “A complete picture of cross-phenotype genetic relationships will require understanding both same and opposite directional effects.”

Identifying which gene variants increase the odds for developing multiple psychiatric disorders provides new clues about the biological pathways that contribute to mental illness, noted computational geneticist Phil H. Lee, PhD, of the Center for Genomic Medicine at MGH and HMS, and who is lead author of the study. “And learning how disorders are related at a biological level may inform how we classify and diagnose mental health conditions.”

The investigators said the collective findings suggest that there are at least two general classes of genetic loci that influence psychiatric disorders. The first comprises a set of pleiotropic genes that confer relatively broad risk of psychiatric disorder by acting at the stage of early neurodevelopment and the establishment of brain circuitry. They appear to “come online” by the second trimester of pregnancy. “The expression and differentiation of this generalized genetic risk into discrete psychiatric syndromes … may then involve direct and/or interactive effects of additional sets of common and rare loci and environmental factors, possibly mediated by epigenetic effects, that shape phenotypic expression via effects on brain structure/function and behavior.”

The authors acknowledged that their studies are not without limitations, and more research will be warranted. Nevertheless, they concluded, “Therapeutic modulation of pleiotropic gene products could have broad-spectrum effects on psychopathology.”

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