Abstract
Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10−4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.
Highlights
Introduction~ 1% of the population, has one of the highest heritability estimates in psychiatry (80%).[1] Genome-wide association studies (GWAS) have been uncovering an increasing number of common variants underlying disease susceptibility, promising valuable insights into pathogenic biological pathways
Schizophrenia, a severe and often chronic disease that affects~ 1% of the population, has one of the highest heritability estimates in psychiatry (80%).[1]
We could replicate the effect of rs9607782 on amygdala activation in an independent control sample using the identical face-matching task (FMT) (x = 30, y = − 4, z = − 11, F = 10.94, Z = 3.04, PFWE(ROI) = 0.025; Figure 3)
Summary
~ 1% of the population, has one of the highest heritability estimates in psychiatry (80%).[1] Genome-wide association studies (GWAS) have been uncovering an increasing number of common variants underlying disease susceptibility, promising valuable insights into pathogenic biological pathways. The largest GWAS to date including 36 989 cases and 113 075 controls identified 125 genetic loci (of which 108 were independent) associated with schizophrenia.[2]. It was suggested that investigating important neurocognitive domains implemented within specific brain circuits could be a promising way for biological psychiatry. Criteria (RDoC) approach[3,4] postulates five major domains (negative valence, positive valence, cognition, social processes and arousal/regulation) containing several subdomains of which many are relevant to schizophrenia. Following the RDoC rationale, in order to uncover biological mechanisms underlying mental illness, these domains warrant investigation at different units of analyses, including genetics and brain circuits.
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