A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder.
OBJECTIVE
Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder.


METHODS
The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London.


RESULTS
The strongest association in the STEP-BD cohort (minimum p=5.5 x 10(-7)) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p<5 x 10(-4)) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2.


CONCLUSIONS
Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.
Perlis
Roy H
RH
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. rperlis@partners.org
Smoller
Jordan W
JW
Ferreira
Manuel A R
MA
McQuillin
Andrew
A
Bass
Nick
N
Lawrence
Jacob
J
Sachs
Gary S
GS
Nimgaonkar
Vishwajit
V
Scolnick
Edward M
EM
Gurling
Hugh
H
Sklar
Pamela
P
Purcell
Shaun
S
D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D016678:Genome; D005838:Genotype; D006801:Humans; D016651:Lithium Carbonate / Q000627:therapeutic use*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics; D055502:Secondary Prevention
D014150:Antipsychotic Agents; D018091:Receptors, AMPA; D016651:Lithium Carbonate; C104722:glutamate receptor ionotropic, AMPA 2