A systematic association mapping on chromosome 6q in bipolar affective disorder--evidence for the melanin-concentrating-hormone-receptor-2 gene as a risk factor for bipolar affective disorder.
Strong evidence of linkage between chromosomal region 6q16-q22 and bipolar affective disorder (BPAD) has previously been reported. We conducted a systematic association mapping of the 6q-linkage interval using 617 SNP markers in a BPAD case-control sample of German descent (cases = 330, controls = 325). In this screening step, 46 SNPs showed nominally significant BPAD-association (P-values between 0.0007 and 0.0484). Although none of the 46 SNPs survived correction for multiple testing, they were genotyped in a second and ethnically matched BPAD sample (cases = 328, controls = 397). At the melanin-concentrating-hormone-receptor-2 (MCHR2) gene, we found nominal association in both the initial and second BPAD samples (combined P = 0.008). This finding was followed up by the genotyping of 17 additional MCHR2-SNPs in the combined sample in order to define our findings more precisely. We found that the MCHR2-locus can be divided into three different haplotype-blocks, and observed that the MCHR2-association was most pronounced in BPAD male patients with psychotic symptoms. In two neighboring blocks, putative risk-haplotypes were found to be 7% more frequent in patients (block II: 23.3% vs. 16.2%, P = 0.005, block III: 39.2% vs. 32.0%, P = 0.024), whereas the putative protective haplotypes were found to be 5-8% less frequent in patients (block II: 11.6% vs. 16.4%, P = 0.041, block III: 30.0% vs. 38.8%, P = 0.007). The corresponding odds ratios (single-marker analysis) ranged between 1.25 and 1.46. Our findings may indicate that MCHR2 is a putative risk factor for BPAD. These findings should be interpreted with caution and replicated in independent BPAD samples.
Abou Jamra
Rami
R
Institute of Human Genetics, University of Bonn, Bonn, Germany. rami.aboujamra@uni-bonn.de
Schulze
Thomas G
TG
Becker
Tim
T
Brockschmidt
Felix F
FF
Green
Elaine
E
Alblas
Margrieta A
MA
Wendland
Jens R
JR
Adli
Mazda
M
Grozeva
Detelina
D
Strohmeier
Jana
J
Georgi
Alexander
A
Craddock
Nick
N
Propping
Peter
P
Rietschel
Marcella
M
Nöthen
Markus M
MM
Cichon
Sven
S
Schumacher
Johannes
J
D000328:Adult; D000341:Affective Disorders, Psychotic / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002875:Chromosomes; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics