¹Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

²Harvard Medical School, Boston, MA, USA

³Whitehead Institute/MIT Center for Genome Research, Cambridge, MA, USA

⁴Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

⁵Division of Neuroscience, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, UK

⁶Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK

Correspondence to: P Sklar, Whitehead Institute/MIT Center for Genome Research, One Kendall Square, Building 300, Cambridge, MA 02139, USA. E-mail: sklar@genome.wi.mit.edu

Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3'. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm.

Molecular Psychiatry (2002) 7, 579-593. doi:10.1038/sj.mp.4001058

genomic; single-nucleotide polymorphism; SNP; linkage; transmission disequilibrium test; susceptibility loci