Genome-wide linkage analysis of multiple measures of neuroticism of 2 large cohorts from Australia and the Netherlands

Abstract

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.

Figure 1

Distribution of a)standardised AU₈₉ Neuroticism scores for those in the genome scan (GS) and those not in the genome scan (No GS) and b) the same but only for those selected to have AU₉₉ scores.

Figure 1

Distribution of a)standardised AU₈₉ Neuroticism scores for those in the genome scan (GS) and those not in the genome scan (No GS) and b) the same but only for those selected to have AU₉₉ scores.

Figure 2

Merlin-Regress linkage results of LOD score (y-axis) for each chromosome (1–22, X) based on a 5 cM grid (x-axis) for mean neuroticism score of the Australian (AU), Dutch (NL) and combined (AU&NL) data sets. Empirical thresholds for suggestive linkage were 1.7 (red horizontal) for AU and AU&NL and 1.9 (blue horizontal) for NL.