title: Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood.
abstract: Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alex
authors.initials: A
authors.lastname: Hatzimanolis
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pallav
authors.initials: P
authors.lastname: Bhatnagar
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Anna
authors.initials: A
authors.lastname: Moes
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Friedman Brain Institute and Department of Genetics and Genomics Science, Institute of Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.|James J. Peters Veterans Affairs Medical Center, Bronx, New York, New York.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Panos
authors.initials: P
authors.lastname: Bitsios
authors.affiliation: University Mental Health Research Institute, Athens, Greece.
authors.forename: Costas N
authors.initials: CN
authors.lastname: Stefanis
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Pulver
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.affiliation: University Mental Health Research Institute, Athens, Greece.|Department of Psychiatry, Eginition Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Smyrnis
authors.affiliation: University Mental Health Research Institute, Athens, Greece.|Department of Psychiatry, Eginition Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Stefanis
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
mesh_terms: D000293:Adolescent; D003072:Cognition Disorders / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
keywords: GWAS; cognition; endophenotype; psychosis; working memory