GWAS Identifies Common Gene Variants that Cause Many Psychiatric Disorders

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Schizophrenia

In the largest study of its kind, researchers at Massachusetts general Hospital have learned that eight psychiatric disorders have common genetic links. Studying GWAS data from healthy controls and individuals with at least one psychiatric disorder, they identified 109 gene variants associated with an increased risk for more than one disorder. Their research was published December 12 in Cell.

The researchers compared the genetic information from 494,162 healthy controls and 232,964 individuals with a least one of eight common psychiatric disorders: anorexia nervosa (AN), obsessive-compulsive disorder (OCD), bipolar disorder (BP), major depression (MD), schizophrenia (SCZ), autism spectrum disorder (AS), ADHD, and Tourette syndrome (TS).

“Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders,” the authors write in their paper. A pleiotropic gene produces multiple effects from a single gene.

Further, the scientists found that the 23 pleiotropic loci are located within genes with heighted expression in the brain throughout life, beginning prenatally in the second trimester, and play important roles in neurodevelopment.

Three categories of genetic structure

Analyzing genome-wide single nucleotide polymorphism (SNP) data, almost 6.8 million common SNPs were identified across all eight disorders. From there, the team sought any common genetic architecture between them. Using statistical exploratory factor analysis, their analysis showed that many disorders share a common genetic structure.

Three genetically-related categories account for 51% of the genetic variation in the disorders; those that involve compulsive behavior (AN, OCD), mood and psychotic disorders (BP, MD, SCZ), and neuro-developmental disorders (AS, ADHD, TS).

“Overall, these results indicate a substantial genetic correlation between multiple disorders along with a higher-level genetic structure that point to broader domains underlying genetic risk to psychopathology,” the authors write.

109 pleiotropic gene regions, 33 previously unknown

While the three categories explain average effects across the disorders, they do not account for more unique cross-disorder effects. Further GWAS analysis produced 146 lead SNPs likely to be involved with shared risk.

Variant-level analyses showed that nearly 75% (109/146) of the genome-wide significant SNPs were pleiotropic, or associated with more than one disorder.  Of these, 83% and 72% involved schizophrenia and bipolar disorder, respectively.

One genetic region, the 18q21.2 region surrounding SNP rs8084351 at the netrin 1 receptor gene DCC, was associated with all eight psychiatric disorders studied. The DCCgene is fundamental in early development of white matter brain connections. The study also showed a link between pleiotropy and genetic effects for three other genes, RBFOX1,BRAF, and KDM7A.

Digging deeper, they team discovered that of the 109 pleiotropic gene regions, 76 were identified in the GWAS of individual disorders but the remaining 33 are novel. These 33 loci have not previously been associated with any of the eight psychiatric disorders studied. The most pleiotropic among these novel loci involve a downstream region of NOX4. It was associated with schizophrenia, bipolar disorder, major depression, ASD, and anorexia nervosa.

Further study revealed 23 multi-purpose loci with at least four of the disorders. These were found in gene regions located in neuronal cell types, especially the frontal or prefrontal regions of the brain. Most of these loci were most highly expressed in the second trimester and thereafter throughout life.  An exception: schizophrenia loci are most highly expressed in the first trimester then decline over the remaining prenatal period and remain stable throughout life.

Same SNP, opposing effects

The researchers found a set of loci with opposing effects on the risk of these psychiatric disorders. Surprisingly, these loci are found in disorders that are genetically similar and have common clinical features.  An example is that a SNP within the MRSA gene had opposing effects on ASD and schizophrenia.

“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 eh level of specific loci and pathways,” the authors write.

They conclude by recommending more comprehensive functional data including single cell transcriptomic and epigenomic profiles across development and brain tissues.

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