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Common Genetic Variation and Schizophrenia Polygenic Risk RESEARCH ARTICLE Neuropsychiatric Genetics Common Genetic Variation and Schizophrenia Polygenic Risk Influence Neurocognitive Performance in Young Adulthood Alex Hatzimanolis,1 Pallav Bhatnagar,2 Anna Moes,2 Ruihua Wang,1 Panos Roussos,3,4 Panos Bitsios,5 Costas N. Stefanis,6 Ann E. Pulver,1 Dan E. Arking,2 Nikolaos Smyrnis,6,7 Nicholas C. Stefanis,6,7 and Dimitrios Avramopoulos1,2* 1Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 3Department 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 4James J. Peters Veterans Affairs Medical Center, Bronx, New York, New York 5Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece 6University Mental Health Research Institute, Athens, Greece 7Department of Psychiatry, Eginition Hospital, University of Athens Medical School, Athens, Greece Manuscript Received: 3 December 2014; Manuscript Accepted: 29 April 2015 Neurocognitive abilities constitute complex traits with consid- erable heritability. Impaired neurocognition is typically ob- How to Cite this Article: served in schizophrenia (SZ), whereas convergent evidence Hatzimanolis A, Bhatnagar P, Moes A, has shown shared genetic determinants between neurocognition Wang R, Roussos P, Bitsios P, Stefanis CN, and SZ. Here, we report a genome-wide association study Pulver AE, Arking DE, Smyrnis N, Stefanis (GWAS) on neuropsychological and oculomotor traits, linked NC, Avramopoulos D. 2015. Common to SZ, in a general population sample of healthy young males Genetic Variation and Schizophrenia ¼ (n 1079). Follow-up genotyping was performed in an identi- Polygenic Risk Influence Neurocognitive ¼ cally phenotyped internal sample (n 738) and an independent Performance in Young Adulthood. cohort of young males with comparable neuropsychological measures (n ¼ 825). Heritability estimates were determined Am J Med Genet Part B 168B:392–401. based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cogni- tive ability and SZ risk polygenic scores were tested utilizing detected and thus additional validation is required. Secondary meta-analysis GWAS results by the Cognitive Genomics Con- permutation-based analysis revealed an excess of strongly asso- sortium (COGENT) and the Psychiatric Genomics Consortium ciated loci among GWAS top-ranked signals for verbal working (PGC-SZ). The GWAS results implicated biologically relevant memory (WM) and antisaccade intra-subject reaction time genetic loci encoding protein targets involved in synaptic neu- variability (empirical P < 0.001), suggesting multiple true-positive rotransmission, although no robust individual replication was single-SNP associations. Substantial heritability was observed This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Alex Hatzimanolis and Pallav Bhatnagar contributed equally to this study. Senior authors Nicholas C. Stefanis and Dimitrios Avramopoulos contributed equally to this study. Conflicts of interest: None. Grant sponsor: NIMH grants; Grant numbers: RO1-MH-085018, RO1-MH-092515; Grant sponsor: Neurosciences Education and Research Foundation. ÃCorrespondence to: Dimitrios Avramopoulos MD, PhD, Institute of Genetic Medicine and Department of Psychiatry, Johns Hopkins University School of Medicine, 733 N. Broadway, BRB-507, Baltimore, MD 21205. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 12 May 2015 DOI 10.1002/ajmg.b.32323 Ó 2015 The Authors American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. 392 HATZIMANOLIS ET AL. 393 for WM performance. Further, sustained attention/vigilance and are associated with neurocognitive weaknesses in clinical and non- WM were suggestively correlated with both COGENT and PGC- clinical populations [Burdick KE et al., 2006; Stefanis NC et al., SZ derived polygenic scores. Overall, these results imply that 2007; Greenwood TA et al., 2011; Hatzimanolis A et al., 2012; common genetic variation explains some of the variability in Walters JT et al., 2013], suggesting that at least some of SZ risk neurocognitive functioning among young adults, particularly variants might have a significant impact on human cognition. WM, and provide supportive evidence that increased SZ genetic More recently, it has been shown that SZ risk genetic loci, when risk predicts neurocognitive fluctuations in the general popula- analyzed as an aggregate polygenic risk score, predict alterations in tion. Ó 2015 The Authors American Journal of Medical Genetics Part B: white matter brain volume, general cognitive ability and working Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. memory related prefrontal brain activation [Terwisscha van Schel- tinga AF et al., 2012; McIntosh AM et al., 2013; Kauppi K et al., Key words: cognition; working memory; endophenotype; 2014]. Several neuropsychological and neurophysiological traits GWAS; psychosis have been proposed as putative endophenotypes (or intermediate phenotypes) for SZ, with potential value in genetic studies as an alternative approach to help identify SZ susceptibility loci [Braff DL et al., 2007; Thaker G, 2008; Greenwood TA et al., 2013, INTRODUCTION Tamminga CA et al., 2014; Ivleva et al., 2014]. The attractiveness of endophenotypes stems from the observation that these traits It is well documented that neurocognition represents a complex are heritable, segregate in SZ families and likely possess a less heritable phenotypic construct with significant genetic influences complex genetic architecture [Gottesman II and Gould TD 2003; across the entire human lifespan [Deary IJ et al., 2012; Plomin R Cannon TD and Keller MC 2006]. Over the past few years, genome- and Deary IJ 2014]. High heritability has been observed in twin- wide association and linkage studies have identified genetic loci based studies for various neurocognitive traits, including episodic associated with SZ candidate neurocognitive endophenotypes memory, working memory and general cognitive ability [Ando J [Almasy L et al., 2008; Greenwood TA et al., 2013; Papassotiro- et al., 2001; Haworth et al., 2010; Owens SF et al., 2011]. Similarly, poulos A et al., 2013; Lencz T et al., 2014; Vaidyanathan U et al., molecular genetic studies have predicted increased heritability 2014]. estimates for general cognitive ability in the general population In the present study, we aimed to uncover through genome-wide by considering the additive effects of thousands common genetic association analyses novel common genetic variants associated markers in the human genome [Plomin R et al., 2013; Benyamin B with candidate endophenotypes for SZ, in healthy young individ- et al., 2014]. Due to the close relationship between neurocognitive uals drawn from the general population. Independent replication deficits and psychiatric illness, nationwide collaborative efforts of the most compelling association results was attempted in two have joined forces in order to investigate the potential contribution additional samples and plausible functional properties of the of common genetic variation to neurocognitive performance, associated variants were tested on human brain gene expression. which may also lead to the identification of specific genetic loci Furthermore, heritability estimates were acquired by assessing the involved in psychiatric nosology [Donohoe G et al., 2013; Lencz T cumulative additive effects of all genome-wide markers. Finally, we et al., 2014]. generated polygenic risk profile scores based on the results of a Individuals with schizophrenia (SZ) underperform in a wide general cognitive ability GWAS meta- analysis and the largest to range of neuropsychological and neurophysiological tasks com- date GWAS meta-analysis for SZ from the Psychiatric Genomics pared to the general population, making neurocognitive im- Consortium (PGC- SZ) [Ripke S et al., 2014], and examined their pairment one of the core features of SZ psychopathology [Kahn contribution to the endophenotypes under investigation. RS and Keefe RS 2013]. Substantial evidence indicates that these deficits usually precede the onset of the full-blown clinical presen- MATERIALS AND METHODS tation of the disease, implying that early cognitive deterioration might represent an important risk factor or prodromal condition of Participants SZ [Kahn RS and Keefe RS 2013; Bora E and Murray RM 2013; A detailed description of the Athens Study of Psychosis Proneness Meier MH et al., 2014]. In addition, family studies have shown that and Incidence of Schizophrenia (ASPIS) has been reported previ- the phenotypic relationship between SZ and neurocognition can be ously [Smyrnis N et al., 2007, 2011; Stefanis NC et al., 2007]. Briefly, attributed to shared genetic effects, which points towards a signifi- the ASPIS examined randomly selected young male conscripts aged cant overlap between the underlying genetic factors inducing
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