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PLoS One. 2014 Jun 30;9(6):e101329. doi: 10.1371/journal.pone.0101329. eCollection 2014.

Systematic fine-mapping of association with BMI and type 2 diabetes at the FTO locus by integrating results from multiple ethnic groups.

Author information

1
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
2
Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
3
Bach Mai Hospital, Hanoi, Vietnam.
4
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
5
Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
6
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan; Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.
7
Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
8
Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.

Abstract

BACKGROUND/OBJECTIVE:

The 16q12.2 locus in the first intron of FTO has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at FTO, we performed a systematic approach consisting of two parts.

METHODS:

The first part is to partition the associated variants into linkage disequilibrium (LD) clusters, followed by conditional and haplotype analyses. The second part is to filter the list of potential causal variants through trans-ethnic comparison.

RESULTS:

We first examined the LD relationship between FTO SNPs showing significant association with type 2 diabetes in Japanese GWAS and between those previously reported in European GWAS. We could partition all the assayed or imputed SNPs showing significant association in the target FTO region into 7 LD clusters. Assaying 9 selected SNPs in 4 Asian-descent populations--Japanese, Vietnamese, Sri Lankan and Chinese (n≤26,109 for BMI association and n≤24,079 for type 2 diabetes association), we identified a responsible haplotype tagged by a cluster of SNPs and successfully narrowed the list of potential causal variants to 25 SNPs, which are the smallest in number among the studies conducted to date for FTO.

CONCLUSIONS:

Our data support that the power to resolve the causal variants from those in strong LD increases consistently when three distant populations--Europeans, Asians and Africans--are included in the follow-up study. It has to be noted that this fine-mapping approach has the advantage of applicability to the existing GWAS data set in combination with direct genotyping of selected variants.

PMID:
24978468
PMCID:
PMC4076329
DOI:
10.1371/journal.pone.0101329
[Indexed for MEDLINE]
Free PMC Article
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