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Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy

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Abstract

One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 × 10−5) for association among Vietnamese patients. Next, we enrolled a case–control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture >80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10−8). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.

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Acknowledgments

We are grateful to all patients and their families who participated in this study. We thank A. Montpetit and A. Bélisle for assistance with high-throughput genotyping and L. Simkin for assistance with genotyping data management. An.A. held a graduate studentship from the Natural Science and Engineering Research Council of Canada (NSERC). Al.A. and L.A. were supported by the Agence Nationale de la Recherche (ANR) of the Ministère Français de l’Éducation Nationale de la Recherche et de la Technologie. E.S. was a Chercheur National du Fonds de la Recherche en Santé du Québec and an International Research Scholar of the Howard Hughes Medical Institute.

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Correspondence to Erwin Schurr.

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A. Alcaïs and E. Schurr share senior authorship.

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Alter, A., Fava, V.M., Huong, N.T. et al. Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy. Hum Genet 132, 107–116 (2013). https://doi.org/10.1007/s00439-012-1227-6

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