A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity.
Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles ('A1' allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5-5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.
Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
T
T
Okada
R
R
Hashimoto
T
T
Numakawa
Y
Y
Iijima
A
A
Kosuga
M
M
Tatsumi
K
K
Kamijima
T
T
Kato
H
H
Kunugi
D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001714:Bipolar Disorder / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000502:physiology; D016022:Case-Control Studies; D002478:Cells, Cultured / Q000378:metabolism; D018900:Dinucleotide Repeats; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; D011993:Recombinant Fusion Proteins