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

Oord, Edwin J. C. G. van den; Kuo, Po-Hsiu; Hartmann, Annette M.; Webb, Bradley T.; Möller, Hans‐Jürgen; Hettema, John M.; Giegling, Ina; Bukszár, József; Rujescu, Dan

doi:10.1001/archpsyc.65.9.1062

Cited by 122 publications

(78 citation statements)

References 89 publications

(92 reference statements)

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“…In addition, no variants overlapped in the four studies. 15,16,42,43 These results can be attributed to the study design and the sample cohort investigated, which included both genders and broad age range. Gender differences in personality traits have been examined in many recent studies.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of the five-factor model of personality in young Korean women

et al. 2013

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Personality is a determinant of behavior and lifestyle associated with health and human diseases. Although personality is known to be a heritable trait, its polygenic nature has made the identification of genetic variants elusive. We performed a genome-wide association study on 1089 Korean women aged 18-40 years whose personality traits were measured with the Revised NEO Personality Inventory for the five-factor model of personality. To reduce environmental factors that may influence personality traits, this study was restricted to young adult women. In the discovery phase, we identified variants of PTPRD (protein tyrosine phosphatase, receptor type D) that associated this gene with the Openness domain. Other genes that were previously reported to be associated with neurological phenotypes were also associated with personality traits. In particular, DRD1 and ORIA2 were linked to Neuroticism, NKAIN2 with Extraversion, HTR5A with Openness and DRD3 with Agreeableness. Data from our replication study of 2090 subjects confirmed the association between ORIA2 and Neuroticism. We first identified and confirmed a novel region on ORIA2 associated with Neuroticism. Candidate genes for psychiatric disorders were also enriched. These findings contribute to our understanding of the genetic architecture of personality traits and provide critical clues to the neurobiological mechanisms that influence them.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study of the five-factor model of personality in young Korean women

et al. 2013

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“…197,198 Similar findings have implicated genetic variants in personality traits such as harm avoidance 199 and neuroticism. 200 Thus, although genetic variants may influence ND directly, they may also do so through their influence on personality traits that are related to cigarette smoking and use of other substances. 191,201 For example, interaction between functional variants in the promoter of the serotonin receptor gene (5-HTTLPR-L/5-HTTLPR-S) and neuroticism was found to influence smoking behavior.…”

Section: General Overviewmentioning

confidence: 99%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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“…Nevertheless, we consider at least the rs2445142 association as a true positive. According to the criteria of Sullivan 53 and van den Oord et al 54 in a replication trial, an uncorrected standard P-value of o0.05 may be used, if association is for the same SNP and phenotype and the direction of effect is the same as in the original report.…”

Section: Discussionmentioning

confidence: 99%

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

Greenbaum¹,

Alkelai²,

Zozulinsky³

et al. 2011

Pharmacogenomics J

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Tardive dyskinesia (TD) is a severe adverse effect of chronic antipsychotic drug treatment. In addition to clinical risk factors, TD susceptibility is influenced by genetic predisposition. Recently, Syu et al. (2010) reported a genome-wide association screening of TD in Japanese schizophrenia patients. The best result was association of single-nucleotide polymorphism (SNP) rs2445142 in the HSPG2 (heparan sulfate proteoglycan 2) gene with TD. In the present study, we report a replication study of the five top Japanese TDassociated SNPs in two Caucasian TD samples. Applying logistic regression and controlling for relevant clinical risk factors, we were able to replicate the association of HSPG2 SNP rs2445142 with TD in a prospective study sample of 179 Americans of European origin by performing a secondary analysis of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genome-wide association study data set, and using a perfect proxy surrogate marker (rs878949; P ¼ 0.039). An association of the 'G' risk allele of HSPG2 SNP rs2445142 with TD was also shown in a sample of Jewish Israeli schizophrenia patients (retrospective, cross-sectional design; P ¼ 0.03). Although the associations were only nominally significant, the findings provide further support for the possible involvement of HSPG2 in susceptibility to TD.

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

Cited by 122 publications

References 89 publications

Genome-wide association study of the five-factor model of personality in young Korean women

Genome-wide association study of the five-factor model of personality in young Korean women

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

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