Publications (14) View all
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Article: A Genome-Wide Association Study Identifies 2 Susceptibility Loci for Crohn's Disease in a Japanese Population.
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ABSTRACT: BACKGROUND & AIMS: Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population. METHODS: We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. RESULTS: We confirmed associations of Crohn's disease with variants inMHC (rs7765379,P = 2.11 x 10(-59)),TNFSF15 (rs6478106,P = 3.87 x 10(-45)), andSTAT3 (rs9891119,P = 2.24 x 10(-14)). We identified 2 new susceptibility loci, on chromosome 4p14 (rs1487630,P = 2.40 x 10(-11), odds ratio = 1.33) and in theSLC25A15-ELF1-WBP4region on 13q14 (rs7329174 in ELF1,P = 5.12 x 10(-9), odds ratio = 1.27). CONCLUSIONS: In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease.Gastroenterology 12/2012; · 11.68 Impact Factor -
Article: Genetic differences in the two main groups of the Japanese population based on autosomal SNPs and haplotypes.
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ABSTRACT: Although the Japanese population has a rather low genetic diversity, we recently confirmed the presence of two main clusters (the Hondo and Ryukyu clusters) through principal component analysis of genome-wide single-nucleotide polymorphism (SNP) genotypes. Understanding the genetic differences between the two main clusters requires further genome-wide analyses based on a dense SNP set and comparison of haplotype frequencies. In the present study, we determined haplotypes for the Hondo cluster of the Japanese population by detecting SNP homozygotes with 388,591 autosomal SNPs from 18,379 individuals and estimated the haplotype frequencies. Haplotypes for the Ryukyu cluster were inferred by a statistical approach using the genotype data from 504 individuals. We then compared the haplotype frequencies between the Hondo and Ryukyu clusters. In most genomic regions, the haplotype frequencies in the Hondo and Ryukyu clusters were very similar. However, in addition to the human leukocyte antigen region on chromosome 6, other genomic regions (chromosomes 3, 4, 5, 7, 10 and 12) showed dissimilarities in haplotype frequency. These regions were enriched for genes involved in the immune system, cell-cell adhesion and the intracellular signaling cascade. These differentiated genomic regions between the Hondo and Ryukyu clusters are of interest because they (1) should be examined carefully in association studies and (2) likely contain genes responsible for morphological or physiological differences between the two groups.Journal of Human Genetics 03/2012; 57(5):326-34. · 2.57 Impact Factor -
Article: Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations.
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ABSTRACT: Obesity is a disorder with a complex genetic etiology, and its epidemic is a worldwide problem. Although multiple genetic loci associated with body mass index, the most common measure of obesity, have been identified in European populations, few studies have focused on Asian populations. Here we report a genome-wide association study and replication studies with 62,245 east Asian subjects, which identified two new body mass index-associated loci in the CDKAL1 locus at 6p22 (rs2206734, P = 1.4 × 10(-11)) and the KLF9 locus at 9q21 (rs11142387, P = 1.3 × 10(-9)), as well as several previously reported loci (the SEC16B, BDNF, FTO, MC4R and GIPR loci, P < 5.0 × 10(-8)). We subsequently performed gene-gene interaction analyses and identified an interaction (P = 2.0 × 10(-8)) between a SNP in the KLF9 locus (rs11142387) and one in the MSTN (also known as GDF8) locus at 2q32 (rs13034723). These findings should provide useful insights into the etiology of obesity.Nature Genetics 01/2012; 44(3):302-6. · 35.53 Impact Factor -
Article: Haplotypes with Copy Number and Single Nucleotide Polymorphisms in CYP2A6 Locus Are Associated with Smoking Quantity in a Japanese Population.
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ABSTRACT: Smoking is a major public health problem, but the genetic factors associated with smoking behaviors are not fully elucidated. Here, we have conducted an integrated genome-wide association study to identify common copy number polymorphisms (CNPs) and single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) in Japanese smokers ([Formula: see text] = 17,158). Our analysis identified a common CNP with a strong effect on CPD (rs8102683; [Formula: see text]) in the 19q13 region, encompassing the CYP2A6 locus. After adjustment for the associated CNP, we found an additional associated SNP (rs11878604; [Formula: see text]) located 30 kb downstream of the CYP2A6 gene. Imputation of the CYP2A6 locus revealed that haplotypes underlying the CNP and the SNP corresponded to classical, functional alleles of CYP2A6 gene that regulate nicotine metabolism and explained 2% of the phenotypic variance of CPD (ANOVA [Formula: see text]-test [Formula: see text]). These haplotypes were also associated with smoking-related diseases, including lung cancer, chronic obstructive pulmonary disease and arteriosclerosis obliterans.PLoS ONE 01/2012; 7(9):e44507. · 4.09 Impact Factor -
Article: PlatinumCNV: a Bayesian Gaussian mixture model for genotyping copy number polymorphisms using SNP array signal intensity data.
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ABSTRACT: We present a statistical model for allele-specific patterns of copy number polymorphisms (CNPs) in commercial single nucleotide polymorphism (SNP) array data. This model is based on the observation that fluorescent signal intensities tend to cluster into clouds of similar allele-specific copy number (ASCN) genotypes at each SNP locus. To capture the tendency of this clustering to be made vague by instrumental errors, our model allows for cluster memberships to overlap each other, according to a Bayesian Gaussian mixture model (GMM). This approach is flexible, allowing for both absolute scale differences and X/Y scale imbalances of fluorescent signal intensities. The resulting model is also robust toward unobserved ASCN genotypes, which can be problematic for ordinary GMMs. We illustrated the utility of the model by applying it to commercial SNP array intensity data obtained from the Illumina HumanHap 610K platform. We retrieved more than 4,000 allele-specific CNPs, though 99% of them showed rather simple allele-specific CNP patterns with only a single aneuploid haplotype among the normal haplotypes. The genotyping accuracy was assessed by two approaches, quantitative PCR and replicated subjects. The results of both of these approaches demonstrated mean genotyping error rates of 1%. We demonstrated a preliminary genome-wide association study of three hematological traits. The result exhibited that it could form the foundation for new, more effective statistical methods for the mapping of both disease genes and quantitative trait loci with genome-wide CNPs. The methods described in this work are implemented in a software package, PlatinumCNV, available on the Internet.Genetic Epidemiology 12/2011; 35(8):831-44. · 3.44 Impact Factor
