Genomewide Association Analysis Followed by a Replication Study Implicates a Novel Candidate Gene for Neuroticism

• DOI: 10.1001/archpsyc.65.9.1062
• Publication Date: 2008-09-01T20:07:36Z
• Authors: Edwin J. C. G. va...; Po-Hsiu Kuo; Annette M. Hartmann; B. Todd Webb; Hans-Jürgen Möller; John M. Hettema; Ina Giegling; József Bukszár; Dan Rujescu
• Keywords: Adult; DNA Replication; Genetic Markers; Male; 0301 basic medicine; Genome; Adolescent; Genotype; Neurotic Disorders; Glycosylphosphatidylinositols; Gene Expression; Middle Aged; Polymorphism, Single Nucleotide; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Humans; Female; Aged

Neuroticism is a trait that reflects a tendency toward negative mood states. It has long been linked to internalizing psychiatric conditions, such as anxiety and depression, and it accounts for much of the substantial comorbidity seen between these disorders.To identify common genetic variants that affect neuroticism to better understand (the comorbidity between) a broad range of psychiatric disorders and to develop effective treatments.More than 420,000 genetic markers were tested for their association with neuroticism in a genomewide association study (GWAS). The GWAS sample consisted of 1227 healthy individuals ascertained from a US national sampling frame and available from the National Institute of Mental Health genetics repository. The most promising markers were subsequently tested in a German replication sample comprising 1880 healthy individuals.A strict definition of replication (same marker, same direction of effects, and same measure) combined with a threshold we proposed previously for declaring significance in genetic studies that ensures a mean probability of producing false-positive findings of less than 10%.The most promising results in the GWAS and replication samples were single-nucleotide polymorphisms (SNPs) in the gene MAMDC1. These SNPs all tagged the same 2 haplotypes and had P values of 10(-5) to 10(-6) in the GWAS sample and of .006 to .02 in the replication sample. Furthermore, the replication involved the same SNPs and the same direction of effects. In a combined analysis of all data, several SNPs were significant according to the threshold that allows for 10% false-positive findings.The small effect sizes may limit the prognostic, diagnostic, and therapeutic use of SNP markers such as those in MAMDC1. However, the present study demonstrates the potential of a GWAS to discover potentially important pathogenic pathways for which clinically more powerful (bio)markers may eventually be developed.