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Accounting for genetic heterogeneity in homozygosity mapping: application to Mendelian susceptibility to mycobacterial disease
  1. Audrey V Grant1,2,
  2. Stéphanie Boisson-Dupuis1,2,3,
  3. Eléonore Herquelot1,2,
  4. Ludovic de Beaucoudrey1,2,
  5. Orchidée Filipe-Santos1,2,
  6. Daniel K Nolan1,2,
  7. Jacqueline Feinberg1,2,
  8. Anne Boland4,
  9. Saleh Al-Muhsen5,
  10. Ozden Sanal6,
  11. Yildiz Camcioglu7,
  12. Ayse Palanduz8,
  13. Sara Sebnem Kilic9,
  14. Jacinta Bustamante1,2,
  15. Jean-Laurent Casanova1,2,3,
  16. Laurent Abel1,2,3
  1. 1Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, U980 Necker Medical School, Paris, France
  2. 2Paris Descartes University, Paris, France
  3. 3St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
  4. 4Centre National de Génotypage, Evry, France
  5. 5Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  6. 6Immunology Division, Hacettepe University Children's Hospital, Ankara, Turkey
  7. 7Department of Pediatrics, Infectious Diseases, Clinical Immunology and Allergy Division, Cerrahpaşa Medical School, Istanbul University, Istanbul, Turkey
  8. 8Department of Family Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
  9. 9Division of Pediatrics, Uludag University School of Medicine, Bursa, Turkey
  1. Correspondence to Laurent Abel, Laboratoire de Génétique Humaine des Maladies Infectieuses, Université Paris Descartes-INSERM U980, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France; laurent.abel{at}


Introduction Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity.

Methods The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations.

Results The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10−3.

Conclusions The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders.

  • Genetic epidemiology
  • infectious disease
  • molecular genetics
  • immunology

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  • Funding The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the Schlumberger Foundation, the BNP Paribas Foundation, the Institut Universitaire de France, and the European Union (grant QLK2-CT-2002-0046), the Rockefeller University Center for Clinical and Translational Science (grant 5UL1RR024143), the Rockefeller University, the Bill and Melinda Gates Foundation, the St Giles Foundation, the Jeffrey Modell Foundation and Talecris Biotherapeutics, and National Institute of Allergy and Immunology (grant 1R01AI089970). AVG was supported in part by the Fondation pour la Recherche Médicale.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Rockefeller University.

  • Provenance and peer review Not commissioned; externally peer reviewed.