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Psychiatric Disorders Fall Into Groups With Shared Genetic Contributors in GWAS Meta-Analysis

NEW YORK – A large international team has profiled genetic risk factors behind eight psychiatric disorders, identifying three sets of conditions that share common genetic contributors.

"These results highlight disparities between our clinically defined classification of psychiatric disorders and underlying biology," co-corresponding author Jordan Smoller, a Harvard psychiatry researcher and director of the psychiatric and neurodevelopmental genetic unit at Massachusetts General Hospital, and co-authors wrote.

As they reported online today in Cell, members of the Cross-Disorder Group of the Psychiatric Genomics Consortium, 23andMe Research Team, the Psychosis Endophenotypes International Consortium, and the Wellcome Case-Control Consortium did a genome-wide association study meta-analysis involving nearly 233,000 individuals diagnosed with one or more of the psychiatric conditions considered, along with more than 494,000 unaffected control individuals.

The search highlighted more than 100 loci that appeared to influence two or more psychiatric disorders apiece, they reported, and follow-up analyses of these pleiotropic genes revealed an over-representation of genes from neurodevelopmental pathways, particularly those showing a jump in expression during development, in the second trimester.

"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," Smoller said in a statement. "To the extent that these genes may have broad effects, they could be potential targets for developing new treatments that might benefit multiple condition."

For their study, the investigators brought together genotyping data spanning almost 6.8 million SNPs for 232,964 cases and 494,162 controls enrolled for prior GWAS of schizophrenia, bipolar disorder, major depression, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), obsessive compulsive disorder (OCD), anorexia nervosa, or Tourette syndrome.

The team's analyses led to almost 150 independent genetic risk loci, including 35 loci not linked to the conditions in the past, and pointed to three broad groups of conditions that appeared to cluster genetically.

One of these groups included conditions classified as early-onset neurodevelopmental disorders, namely ADHD, ASD, and Tourette syndrome, the investigators explained. Likewise, OCD and anorexia nervosa — conditions marked by compulsive behaviors — grouped together genetically, while a third group included the "mood and psychotic disorders," schizophrenia, bipolar disorder, and major depression.

While 109 of the psychiatric disorder-associated loci showed ties to two conditions, they noted that nearly two-dozen loci were linked to at least four psychiatric conditions. In contrast, 11 loci appeared to have antagonistic or opposing effects across the conditions considered.

By incorporating available gene function clues and gene expression patterns in post-mortem samples from different parts of the brain during pre- and post-natal development, the authors determined that "genes associated with multiple psychiatric disorders are disproportionately associated with biological pathways related to neurodevelopment and exhibit distinctive gene expression patterns, with enhanced expression beginning in the second prenatal trimester and persistently elevated expression relative to less pleiotropic genes."

These and other data suggested that it may be possible to broadly impact processes involved in psychiatric disease development by identifying treatments that may impact the activity of such pleiotropic genes. Moreover, they noted that the current study "underscores the need for more comprehensive functional data including single-cell transcriptomic and epigenetic profiles across development and brain tissues."

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