Haplotypic analysis of Wellcome Trust Case Control Consortium data.
We applied a recently developed multilocus association testing method (localized haplotype clustering) to Wellcome Trust Case Control Consortium data (14,000 cases of seven common diseases and 3,000 shared controls genotyped on the Affymetrix 500 K array). After rigorous data quality filtering, we identified three disease-associated loci with strong statistical support from localized haplotype cluster tests but with only marginal significance in single marker tests. These loci are chromosomes 10p15.1 with type 1 diabetes (p = 5.1 x 10(-9)), 12q15 with type 2 diabetes (p = 1.9 x 10(-7)) and 15q26.2 with hypertension (p = 2.8 x 10(-8)). We also detected the association of chromosome 9p21.3 with type 2 diabetes (p = 2.8 x 10(-8)), although this locus did not pass our stringent genotype quality filters. The association of 10p15.1 with type 1 diabetes and 9p21.3 with type 2 diabetes have both been replicated in other studies using independent data sets. Overall, localized haplotype cluster analysis had better success detecting disease associated variants than a previous single-marker analysis of imputed HapMap SNPs. We found that stringent application of quality score thresholds to genotype data substantially reduced false-positive results arising from genotype error. In addition, we demonstrate that it is possible to simultaneously phase 16,000 individuals genotyped on genome-wide data (450 K markers) using the Beagle software package.
Browning
Brian L
BL
Department of Statistics, The University of Auckland, Private Bag 92019, Auckland, New Zealand, b.browning@auckland.ac.nz.
Browning
Sharon R
SR
D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D005819:Genetic Markers