title: Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs.
abstract: OBJECTIVE
  Multiple linkage and association studies have suggested chromosome 8q24 as a promising candidate region for bipolar disorder (BP). We performed a detailed association analysis assessing the contribution of common genetic variation in this region to the risk of BP.
  
  
  METHODS
  We analyzed 2,756 single nucleotide polymorphism (SNP) markers in the chromosome 8q24 region of 3,512 individuals from 737 families. In addition, we extended genotype imputation methods to family-based data and imputed 22,725 HapMap SNPs in the same region on 8q24. We applied a family-based method to test 15,552 high-quality genotyped or imputed SNPs for association with BP.
  
  
  RESULTS
  Our association analysis identified the most significant marker (p=4.80 × 10(-5) ), near the gene encoding potassium voltage-gated channel KQT-like protein (KCNQ3). Other marginally significant markers were located near adenylate cyclase 8 (ADCY8) and ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3GAL1).
  
  
  CONCLUSIONS
  We developed an approach to apply MACH imputation to family-based data, which can increase the power to detect association signals. Our association results showed suggestive evidence of association of BP with loci near KCNQ3, ADCY8, and ST3GAL1. Consistent with genes identified by genome-wide association studies for BP, our results suggest the involvement of ion channelopathy in BP pathogenesis. However, common variants are insufficient to explain linkage findings in 8q24; other genetic variation should be explored.
authors.affiliation: Center for Computational Medicine and Bioinformatics Center for Statistical Genetics, Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Xiang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Sliwerska
authors.forename: Melvin G
authors.initials: MG
authors.lastname: McInnis
authors.forename: Margit
authors.initials: M
authors.lastname: Burmeister
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zöllner
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics; D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8; D005190:Family; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D051659:KCNQ3 Potassium Channel / Q000235:genetics; D008297:Male; D008390:Markov Chains; D020641:Polymorphism, Single Nucleotide; D012799:Sialyltransferases / Q000235:genetics; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D005819:Genetic Markers; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D012799:Sialyltransferases; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human