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TMPRSS9 and GRIN2B Are Associated with Neuroticism: a Genome-Wide Association Study in a European Sample

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Abstract

Major depression disorder (MDD) is a complex and chronic disease that ranks fourth as cause of disability worldwide. About 14 million adults in the USA are believed to have MDD, and an estimated 75 % attempt suicide making MDD a major public health problem. Neuroticism has been recognized as an endophenotype of MDD; however, few genome-wide association (GWA) analyses of neuroticism as a quantitative trait have been reported to date. The aim of this study is to identify genome-wide genetic variants affecting neuroticism using a European sample. A linear regression model was used to analyze the association with neuroticism as a continuous trait in the Netherlands Study of Depression and Anxiety and Netherlands Twin Registry population-based sample of 2,748 individuals with Perlegen 600K single nucleotide polymorphisms (SNPs). In addition, the neuroticism-associated genes/loci of the top 20 SNPs (p < 10−4) were examined with anti-social personality disorder (ASPD) in an Australian twin family study. Through GWA analysis, 32 neuroticism-associated SNPs (p < 10−4) were identified. The most significant association was observed with SNP rs4806846 within the TMPRSS9 gene (p = 7.79 × 10−6) at 19p13.3. The next best signal was in GRIN2B gene (rs220549, p = 1.05 × 10−5) at 12p12. In addition, several SNPs within GRIN2B showed borderline associations with ASPD in the Australian sample. In conclusion, these results provide a possible genetic basis for the association with neuroticism. Our findings provide a basis for replication in other populations to elucidate the potential role of these genetic variants in neuroticism and MDD along with a possible relationship between ASPD and neuroticism.

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Acknowledgments

Funding support for Major Depression: Stage 1 Genomewide Association in Population-Based Samples was provided by NWO: genetic basis of anxiety and depression (904-61-090), resolving cause and effect in the association between exercise and well-being (904-61-193), twin-family database for behavior genomics studies (480-04-004), twin research focusing on behavior (400-05-717), Center for Medical Systems Biology (NWO Genomics), Spinozapremie (SPI 56-464-14192), Centre for Neurogenomics and Cognitive Research (CNCR-VU), genome-wide analyses of European twin and population cohorts (EU/QLRT-2001-01254), genome scan for neuroticism (NIMH R01 MH059160), Geestkracht program of ZonMW (10-000-1002), and matching funds from universities and mental health care institutes involved in NESDA (GGZ Buitenamstel-Geestgronden, Rivierduinen, University Medical Center Groningen, GGZ Lentis, GGZ Friesland, GGZ Drenthe). Major funding for this project is from the Genetic Association Information Network of the Foundation for the US National Institutes of Health, a public–private partnership between the NIH and Pfizer Inc., Affymetrix Inc. and Abbott Laboratories. The genotyping of samples was provided through the GAIN. The dataset used for the analyses described in this manuscript was obtained from the database of Genotype and Phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000020.v2.p1. Samples and associated phenotype data for Major Depression: Stage 1 Genomewide Association in Population-Based Samples were provided by Dr Patrick F. Sullivan. The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gap through dbGaP accession number: phs000125.v1.p1. The dataset for replication study was obtained from the CIDA database found at http://www.ncbi.nlm.nih.gov/projects/gap/ through the dbGAP accession number Study Accession: phs000181.v1.p1. Funding support for the (CIDR-OZALC GWAS) was provided through the Center for Inherited Disease Research (CIDR) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). CIDR-OZALC GWAS is a genome-wide association studies funded as part of the NIAAA grant 5 R01 AA013320-04. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the CIDR-OZALC GWAS. Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the MARC: Risk Mechanisms in Alcoholism and Comorbidity (MARC; P60 AA011998-11). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). This work was partially supported by the College of Public Health and the School of Graduate Studies at the East Tennessee State University (To N. Aragam). This study was approved by Internal Review Board, East Tennessee State University.

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  1. Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN, 37614-1700, USA

    Nagesh Aragam, Ke-Sheng Wang, James L. Anderson & Xuefeng Liu

  2. Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Nagesh Aragam

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  1. Nagesh Aragam
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  2. Ke-Sheng Wang
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Correspondence to Ke-Sheng Wang.

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Aragam, N., Wang, KS., Anderson, J.L. et al. TMPRSS9 and GRIN2B Are Associated with Neuroticism: a Genome-Wide Association Study in a European Sample. J Mol Neurosci 50, 250–256 (2013). https://doi.org/10.1007/s12031-012-9931-1

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