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Genome-Wide Linkage Analysis of Multiple Measures of Neuroticism of 2 Large Cohorts From Australia and the Netherlands
Naomi R. Wray, PhD;
Christel M. Middeldorp, MD;
Andrew J. Birley, PhD;
Scott D. Gordon, PhD;
Patrick F. Sullivan, MD, FRANZCP;
Peter M. Visscher, PhD;
Dale R. Nyholt, PhD;
Gonneke Willemsen, PhD;
Eco J. C. de Geus, PhD;
P. Eline Slagboom, PhD;
Grant W. Montgomery, PhD;
Nicholas G. Martin, PhD;
Dorret I. Boomsma, PhD
Arch Gen Psychiatry. 2008;65(6):649-658.
Context People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the etiology of these important psychiatric disorders.
Objectives To undertake a comprehensive genome-wide linkage study of neuroticism using large study samples that have been measured multiple times and to compare the results between countries for replication and across time within countries for consistency.
Design Genome-wide linkage scan.
Setting Twin individuals and their family members from Australia and the Netherlands.
Participants Nineteen thousand six hundred thirty-five sibling pairs completed self-report questionnaires for neuroticism up to 5 times over a period of up to 22 years. Five thousand sixty-nine sibling pairs were genotyped with microsatellite markers.
Methods Nonparametric linkage analyses were conducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time-specific measures of neuroticism from each country to investigate consistency of linkage results.
Results Three chromosomal regions exceeded empirically derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 Kosambi cM (cM) (Dutch study sample), 14q 103 cM (Dutch study sample), and 18q 117 cM (combined Australian and Dutch study sample), but only 14q retained significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and 1 (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice.
Conclusions Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbor causal variants for neuroticism and its related psychiatric disorders and can inform prioritization of results from genome-wide association studies.
Author Affiliations: Queensland Institute of Medical Research, Brisbane, Australia (Drs Wray, Birley, Gordon, Visscher, Nyholt, Montgomery, and Martin); Vrije Universiteit, Amsterdam (Drs Middeldorp, Willemsen, de Geus, and Boomsma), and Leiden University Medical Center, Leiden (Dr Slagboom), the Netherlands; and University of North Carolina, Chapel Hill (Dr Sullivan).
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