title: Systematic fine-mapping of association with BMI and type 2 diabetes at the FTO locus by integrating results from multiple ethnic groups.
abstract: 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.
authors: Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Koichi
authors: K
authors: Akiyama
authors: Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Fumihiko
authors: F
authors: Takeuchi
authors: Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Masato
authors: M
authors: Isono
authors: Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
authors: Sureka
authors: S
authors: Chakrawarthy
authors: Bach Mai Hospital, Hanoi, Vietnam.
authors: Quang Ngoc
authors: QN
authors: Nguyen
authors: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Wanqing
authors: W
authors: Wen
authors: Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors: Ken
authors: K
authors: Yamamoto
authors: 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.
authors: Tomohiro
authors: T
authors: Katsuya
authors: Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
authors: Anuradhani
authors: A
authors: Kasturiratne
authors: Bach Mai Hospital, Hanoi, Vietnam.
authors: Son Thai
authors: ST
authors: Pham
authors: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Wei
authors: W
authors: Zheng
authors: Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Yumi
authors: Y
authors: Matsushita
authors: Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Miyako
authors: M
authors: Kishimoto
authors: Bach Mai Hospital, Hanoi, Vietnam.
authors: Loi Doan
authors: LD
authors: Do
authors: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Xiao-Ou
authors: XO
authors: Shu
authors: Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
authors: Ananda R
authors: AR
authors: Wickremasinghe
authors: Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Hiroshi
authors: H
authors: Kajio
authors: Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Norihiro
authors: N
authors: Kato
mesh_terms: D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D044466:Asian People; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human