Detecting genome wide haplotype sharing using SNP or microsatellite haplotype data

Abstract

Genome wide association studies using high throughput technology are already being conducted despite the significant hurdles that need to be overcome (Nat Rev Genet 6:95-108, 2005; Nat Rev Genet 6:109-118, 2005). Methods for detecting haplotype association signals in genome wide haplotype datasets are as yet very limited. Much methodological research has already been devoted to linkage disequilibrium (LD) fine mapping where the focus is the identification of the disease locus rather than the detection of a disease signal. Applications of these approaches to genome wide scanning are limited by the strong model assumptions of the sharing process, which lead to computational complexity. We describe a new algorithm for the initial identification of disease susceptibility loci in genome wide haplotype association studies. Excess sharing of ancestral haplotypes, which indicates the presence of a disease locus, is detected with a simple, easy to interpret, chi2 based statistic. The method allows genome wide scanning for qualitative traits within reasonable computational timeframes and can serve as a first pass analysis prior to the usage of likelihood based methods, providing candidate regions and inferred susceptibility haplotypes. Our method makes no assumptions regarding the population history or the pattern of background LD. Statistical significance is evaluated with permutation tests. The method is illustrated on simulated and real data where it is applied to simple (cystic fibrosis) and complex disease (multiple sclerosis) examples. The statistic has low type I error and greater power to map disease loci over conventional single marker tests for low to moderate levels of LD.

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

“…This finding suggests that, although ASD probands may not have a higher burden of homozygous segments compared to parental controls, the probands display a much higher degree of haplotype sharing within overlapping homozygous regions. Excess haplotype sharing often indicates the presence of a disease locus (Bahlo et al 2006), an observation that forms the basis of the current study. Two distinct types of rHH were identified in the affected cohort; (1) homozygous segments with a haplotype that is present in ASD probands but absent in parental controls and (2) homozygous segments with a haplotype that is present at a higher frequency in ASD cases compared to parental controls.…”

SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians

“…In the current study, the HAPLOCLUSTERS program (23) was used to investigate haplotype sharing (identical‐by‐descent across families) in extended HLA haplotypes encompassing the 26 SNPs and five microsatellite markers mapped previously to an 865‐kb putative risk interval (D6S1683–D6S265) (13). As we had previously mapped the causal MS susceptibility allele to the telomeric end of the extended DRB1*15 haplotype ( A*3‐B*7‐DRB1*15 ), tests of association with disease susceptibility were performed only for SNP and microsatellite alleles tagging this haplotype vs the other alleles at each marker.…”

Genetic association of sequence variation in exon 3 of the swine leukocyte antigen-DQA gene with piglet diarrhea in Large White, Landrace, and Duroc piglets

“…This gene contains four exons and three introns: exon 1 encodes a signal peptide, exons 2 and 3 encode corresponding external cellular a1 and a2 domains, and exon 4 encodes both the transmembrane and cytoplasmic domains. Although recent study has increased our knowledge of the association between DQA exon 2 genetic variation and piglet diarrhea (Yang et al, 2013;Huang et al, 2015;Liu et al, 2015b), it is widely accepted that polymorphic loci do not act alone in determining disease resistance, but rather as part of an intrinsic network (Stumpf, 2004;Bahlo et al, 2006). As both SLA-DRA and SLA-DRA-DQA haplotypes are linked to diarrhea resistance in Large White, Landrace, Duroc, and Yantai Black piglets (Yang et al, 2014, it is probable that variants in additional SLA-DQA exon coding regions act as a linked intrinsic network to contribute to diarrhea disease.…”