Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT)

Abstract

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia, evident prior to full illness onset and independent of medication. The possibility of genetic overlap between risk for schizophrenia and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with schizophrenia; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of schizophrenia have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common SNPs of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for schizophrenia. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from 9 non-clinical cohorts comprising the COGENT consortium) to four schizophrenia case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for schizophrenia were associated with lower general cognitive ability. Additionally, using our large cognitive meta-analytic dataset, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with schizophrenia susceptibility. Results provide molecular confirmation of the genetic overlap between schizophrenia and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood

“…Although we could not replicate individual single‐SNP associations, likely due to small effect sizes of the respective variants, the cumulative effect of multiple SNPs, as indexed by the computed polygenic score, shows correlation with WM which is central to general cognitive ability and a key component of the composite phenotypic construct analyzed by COGENT [Lencz T et al, 2014]. Applying the same polygenic strategy, we explored the extent of the overlapping genetic determinants between neurocognitive performance and SZ risk, if any.…”

“…Polygenic risk scores (PRS) based on the latest meta‐analysis GWAS results on general cognitive ability (Cognitive Genomics ConsorTium, COGENT) and SZ (Psychiatric Genomics Consortium, PGC‐SZ) [Lencz T et al, 2014; Ripke S et al, 2014] were generated following the procedure described by the International Schizophrenia Consortium [Purcell SM et al, 2009]. SNPs were filtered by applying seven P ‐value thresholds ( P T  < 0.0001, P T  < 0.001, P T  < 0.01, P T  < 0.05, P T  < 0.1, P T  < 0.3, P T  < 0.5) to PGC‐SZ GWAS summary statistics (discovery sample).…”

“…Similarly, molecular genetic studies have predicted increased heritability estimates for general cognitive ability in the general population by considering the additive effects of thousands common genetic markers in the human genome [Plomin R et al, 2013; Benyamin B et al, 2014]. Due to the close relationship between neurocognitive deficits and psychiatric illness, nationwide collaborative efforts have joined forces in order to investigate the potential contribution of common genetic variation to neurocognitive performance, which may also lead to the identification of specific genetic loci involved in psychiatric nosology [Donohoe G et al, 2013; Lencz T et al, 2014]. …”

“…The attractiveness of endophenotypes stems from the observation that these traits are heritable, segregate in SZ families and likely possess a less complex genetic architecture [Gottesman II and Gould TD 2003; Cannon TD and Keller MC 2006]. Over the past few years, genome‐wide association and linkage studies have identified genetic loci associated with SZ candidate neurocognitive endophenotypes [Almasy L et al, 2008; Greenwood TA et al, 2013; Papassotiropoulos A et al, 2013; Lencz T et al, 2014; Vaidyanathan U et al, 2014]. …”

Genetic studies of schizophrenia: an update

“…MIR137 targets multiple genes involved in SCZ, bipolar disorder, and autism [86][87][88] . While the extent of sharing between these disorders may differ, the pleiotropic effects seem to extend beyond these traditional psychiatric disorders [89][90][91][92] .…”