Abstract
Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacrossP=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacrossP=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.
Highlights
Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder affect tens of millions of people worldwide
Genome-wide association studies (GWAS), structural variant analyses and genome sequencing studies have identified that common single-nucleotide variants (SNVs), low penetrant rare SNVs, moderate to high penetrant copy number variants (CNVs) and potentially causal de novo mutations each play a role in the genetic etiology of SCZ and BD and, to a lesser extent, in recurrent major depressive disorder (rMDD).[1,2,3,4]
We found that a significantly higher burden of singleton disruptive variants in the Disrupted in schizophrenia 1 (DISC1) Interactome was associated with lower cognitive ability assessed by Moray House Test (MHT) scores at age 11
Summary
Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) affect tens of millions of people worldwide. These disorders are moderately heritable and family history is a strong predictor of risk. Genome-wide association studies (GWAS), structural variant analyses and genome sequencing studies have identified that common single-nucleotide variants (SNVs), low penetrant rare SNVs, moderate to high penetrant copy number variants (CNVs) and potentially causal de novo mutations each play a role in the genetic etiology of SCZ and BD and, to a lesser extent, in rMDD.[1,2,3,4]. There is strong evidence for shared genetic risk across traditional diagnostic boundaries supporting the observation of ‘mixed’ diagnoses families.[5,6] GWAS studies capture common, ancient variation and point to an additive, polygenic architecture that transcends psychiatric diagnoses to predict cognitive ability variables.[1,7,8] Lower cognitive function, both premorbid and postonset, has been associated with these disorders, and recently polygenic risk score analysis has suggested a small, but significant, genetic correlation between risk for major mental illness and cognitive ability.[9]
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