Abstract
Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay recall verbal memory. In particular, one locus (rs9896243) associated with long-delay recall was mapped to the NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) gene, indicating the role of membrane fusion in adolescent verbal memory. Based on the GWAS in the European subset, we estimated the SNP-heritability to be 15% to 29% for the three verbal memory traits. We found that verbal memory was genetically correlated with schizophrenia, providing further evidence supporting verbal memory as an endophenotype for psychosis.
Highlights
IntroductionThe latest genome-wide association studies (GWASs) have discovered 270 genomic loci associated with schizophrenia and 64 associated with bipolar disorder [3,4], the mechanisms through which genetic variation in those loci contributes to disease risk are unknown
Summary statistics of the genome-wide association studies (GWASs) results of the three verbal memory traits in the whole sample were uploaded to the platform of Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA) [57]
SNPs with r2 ≥ 0.6 were considered to be in linkage disequilibrium (LD) with the lead SNPs and their good proxies
Summary
The latest genome-wide association studies (GWASs) have discovered 270 genomic loci associated with schizophrenia and 64 associated with bipolar disorder [3,4], the mechanisms through which genetic variation in those loci contributes to disease risk are unknown. One potential solution to this issue is by investigating the endophenotypes of psychosis, which are biomarkers of the disease that lie closer to the genetic effects and are thought to be part of the mechanistic path from genetic variation to clinical manifestation [5,6]. Previous meta-analyses have found prominent deficits in verbal memory in patients with schizophrenia (Cohen’s d = −1.20 to −0.85 [12]) and bipolar disorder (Cohen’s d = −0.56 to −0.50 [13])
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