Original Investigation

Human Genetics

, Volume 132, Issue 1, pp 107-116

First online:

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

  • Andrea AlterAffiliated withMcGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health CentreDepartments of Medicine and Human Genetics, McGill University
  • , Vinicius Medeiros FavaAffiliated withMcGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health CentreDepartments of Medicine and Human Genetics, McGill University
  • , Nguyen Thu HuongAffiliated withHospital for Dermato-Venereology
  • , Meenakshi SinghAffiliated withDepartment of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences
  • , Marianna OrlovaAffiliated withMcGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health CentreDepartments of Medicine and Human Genetics, McGill University
  • , Nguyen Van ThucAffiliated withHospital for Dermato-Venereology
  • , Kiran KatochAffiliated withCentral JALMA Institute of Leprosy and Other Infectious Diseases
  • , Vu Hong ThaiAffiliated withHospital for Dermato-Venereology
  • , Nguyen Ngoc BaAffiliated withHospital for Dermato-Venereology
    • , Laurent AbelAffiliated withLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche MédicaleUniversity Paris Descartes, Sorbonne Paris Cité, Necker Medical SchoolSaint Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University
    • , Narinder MehraAffiliated withDepartment of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences
    • , Alexandre AlcaïsAffiliated withLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche MédicaleUniversity Paris Descartes, Sorbonne Paris Cité, Necker Medical SchoolSaint Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityCIC-0901, Cochin-NeckerUnité de Recherche Clinique, AP-HP, Hôpital Tarnier
    • , Erwin SchurrAffiliated withMcGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health CentreDepartments of Medicine and Human Genetics, McGill UniversityMontreal General Hospital Research Institute Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

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.