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