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| Session Information |
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| Session Title: . Mapping, Linkage and Linkage Disequilibrium Session Type: Poster |
| Session Location: Exhibit Hall II, Convention Center Session Time: Thu 7:00AM-3:30PM |
| Abstract Information |
| Program Number: 1976/T Poster Board Number:525 Presentation Time: Thu, Oct 22, 2009, 1:00PM-2:00PM |
| Keywords: Mapping, Linkage and Linkage Disequilibrium, KW080 - GENOME-WIDE ASSOCIATION, KW100 - MAPPING COMPLEX TRAITS, KW041 - DIABETES, KW140 - POPULATION GENETICS, KW084 - HAPLOTYPE |
| Abstract Content |
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Ethnic diversity in fine mapping of the susceptibility loci G6PC2-ABCB11 for fasting glucose and CDKAL1 for type 2 diabetes. F. Takeuchi1, T. Katsuya2, S. Chakrewarthy3, K. Yamamoto4, T. Fujisawa2, E. Nakashima5, K. Ohnaka6, H. Ikegami7, T. Sugiyama8, T. Nabika9, A. Kasturiratne3, S. Yamaguchi9, S. Kono6, R. Takayanagi6, Y. Yamori10, S. Kobayashi9, T. Ogihara11, A. de Silva3, R. Wickremasinghe3, N. Kato1 for the NIBIO GWA Study 1) Research Institute, International Medical Center of Japan; 2) Osaka University Graduate School of Medicine; 3) University of Kelaniya; 4) Medical Institute of Bioregulation, Kyushu University; 5) Nagoya University Graduate School of Medicine; 6) Graduate School of Medical Sciences, Kyushu University; 7) Kinki University School of Medicine; 8) Institute for Adult Diseases, Asahi Life Foundation; 9) Shimane University School of Medicine; 10) Research Institute for Production Development; 11) Osaka General Medical Center. Objective. Recently, genome-wide association (GWA) studies have successfully identified numerous loci influencing disease susceptibility or quantitative traits. To discern the causal variant(s), we need to enumerate potential causal variants and narrow them down in the region of interest. Along this line, we compared populations of European and Asian descent to refine association signals at two susceptibility lociG6PC2-ABCB11 and CDKAL1for glycemic traits previously identified by GWA studies of Europeans. Methods. In the G6PC2-ABCB11 region, we examined fasting glucose association in 776 non-diabetic Japanese samples who are part of our ongoing GWA study, and chose index SNPs for further genotyping in the general populations of Japanese (N = 4,813) and Sri Lankans (N = 2,319). In the CDKAL1 region, based on our GWA study in the Japanese, we compared haplotypes and their association with type 2 diabetes (T2D) between the Japanese and Europeans. SNPs representing the associations were tested in case-control samples of Japanese (N = 2,774) and Sri Lankans (N = 1,114). Results. We could confirm the association of fasting glucose with variants at G6PC2-ABCB11. In addition to the reported SNP rs560887, we identified significant associations at a novel variant rs3755157 in both the Japanese ( = 0.057 mmol/l, P = 2.6 × 10-8) and Sri Lankans ( = 0.069 mmol/l, P = 0.001), with allelic heterogeneity implicated between the two SNPs. In the CDKAL1 region, the use of ethnic diversity in linkage disequilibrium (LD) pattern helped to refine T2D association signals to an index SNP rs9368222. Furthermore, cross-population filtering could appreciably reduce potential causal variants; i.e., from 79 to 7 in the G6PC2-ABCB11 region and from 69 to 3 in the CDKAL1 region. Conclusions. It has been argued that populations of African descent may be advantageous for fine mapping but statistical power could be limiting due to the unavailability of sufficiently large samples and/or a smaller effect size. Instead, our data demonstrate that ethnic diversity in the pattern and strength of LD between populations of European and Asian descent can allow us to appreciably reduce potential causal variants and also to focus on most promising variants for functional follow-up. |
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