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


OBJECTIVE
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.


METHODS
Genome-wide linkage scan.


METHODS
Twin individuals and their family members from Australia and the Netherlands.


METHODS
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.
Department of Genetic Epidemiology, Queensland Institute of Medical Research, 300 Herston Rd, Brisbane, Australia 4029. naomi.wray@qimr.edu.au
Naomi R
NR
Wray
Christel M
CM
Middeldorp
Andrew J
AJ
Birley
Scott D
SD
Gordon
Patrick F
PF
Sullivan
Peter M
PM
Visscher
Dale R
DR
Nyholt
Gonneke
G
Willemsen
Eco J C
EJ
de Geus
P Eline
PE
Slagboom
Grant W
GW
Montgomery
Nicholas G
NG
Martin
Dorret I
DI
Boomsma
D000293:Adolescent; D000328:Adult; D001315:Australia; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D015331:Cohort Studies; D015897:Comorbidity; D003431:Cross-Cultural Comparison; D004200:Diseases in Twins / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D005260:Female; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008137:Longitudinal Studies; D008297:Male; D009426:Netherlands; D009497:Neurotic Disorders / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D010554:Personality Disorders / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D010555:Personality Inventory; D012737:Sex Factors