title: Accounting for genetic heterogeneity in homozygosity mapping: application to Mendelian susceptibility to mycobacterial disease.
abstract: BACKGROUND
  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.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Université Paris Descartes-INSERM U980, Faculté de Médecine Necker, 156 rue de Vaugirard, Paris, France.
authors.forename: Audrey V
authors.initials: AV
authors.lastname: Grant
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Eléonore
authors.initials: E
authors.lastname: Herquelot
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Orchidée
authors.initials: O
authors.lastname: Filipe-Santos
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nolan
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Camcioglu
authors.forename: Ayse
authors.initials: A
authors.lastname: Palanduz
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
mesh_terms: D005190:Family; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D009164:Mycobacterium Infections / Q000235:genetics*