Anxiety and comorbid measures associated with PLXNA2.
BACKGROUND
Reduction in adult neurogenesis has been proposed as a mechanism for onset of depression. Semaphorins and their coreceptors, plexins, have been implicated in nervous system development and in adult neurogenesis. A recent genomewide association study of schizophrenia identified a variant of the gene encoding plexin A2 (PLXNA2) to be most consistently associated across study samples. Common genetic liabilities have been reported between psychiatric and psychological measures, but few examples exist of common genetic variants.


OBJECTIVE
To perform a genetic association study between 6 single nucleotide polymorphisms from the PLXNA2 gene (rs3736963, rs2767565, rs752016, rs1327175, rs2478813, and rs716461) and anxiety, depression, neuroticism, and psychological distress.


METHODS
Extreme discordant and concordant siblings.


METHODS
Australia.


METHODS
Study participants were selected with respect to extreme neuroticism scores from a population cohort of 18 742 twin individuals and their siblings. The participants and their parents (if blood or buccal samples were available) were genotyped, for a total of 2854 genotyped individuals from 990 families. Of these, 624 individuals with a diagnosis of anxiety or depression from 443 families were used in the association analysis.


METHODS
All the participants completed the Composite International Diagnostic Interview, the 23-item Neuroticism scale of the revised Eysenck Personality Questionnaire, and the 10-item Kessler Psychological Distress Scale. Diagnoses of DSM-IV depression and anxiety were determined from the Composite International Diagnostic Interview.


RESULTS
There was evidence of an allelic association between rs2478813 (and other single nucleotide polymorphisms correlated with it) and anxiety, depression, neuroticism, and psychological distress; the association with anxiety is significant after Bonferroni correction for multiple testing (empirical P<.001). The mouse ortholog of PLXNA2 is located in a highly significant linkage region previously reported for anxiety in mice.


CONCLUSIONS
PLXNA2 is a candidate for causal variation in anxiety and in other psychiatric disorders through its comorbidity with anxiety.
Wray
Naomi R
NR
Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, QLD 4029, Australia. naomi.wray@qimr.edu.au
James
Michael R
MR
Mah
Steven P
SP
Nelson
Matthew
M
Andrews
Gavin
G
Sullivan
Patrick F
PF
Montgomery
Grant W
GW
Birley
Andrew J
AJ
Braun
Andreas
A
Martin
Nicholas G
NG
D001008:Anxiety Disorders / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D001315:Australia / Q000453:epidemiology; D002874:Chromosome Mapping; D015331:Cohort Studies; D015897:Comorbidity; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004200:Diseases in Twins / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009497:Neurotic Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D010375:Pedigree; D010554:Personality Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D011956:Receptors, Cell Surface / Q000235:genetics*; D039961:Semaphorins / Q000235:genetics; D035781:Siblings; D013315:Stress, Psychological / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics
D009419:Nerve Tissue Proteins; C515995:PLXNA2 protein, human; D011956:Receptors, Cell Surface; D039961:Semaphorins