title: Finding genetic contributions to sporadic disease: a recessive locus at 12q24 commonly contributes to patent ductus arteriosus.
abstract: The causes of many sporadic diseases are unexplained; the contribution of recessive loci with reduced penetrance is one possibility that has been difficult to explore. We describe an approach to this problem by first searching for diseases with higher prevalence in populations with high rates of consanguinity, then determining whether disease cases are more commonly the product of consanguinous union than controls in such populations, followed by analysis of genetic linkage in consanguinous cases. We demonstrate the utility of this approach by investigation of congenital heart disease in Iran. We found that patent ductus arteriosus (PDA), a common congenital heart disease, accounts for a higher fraction of congenital heart disease in Iran (15%) than in the United States (2-7%). Moreover, Iranian PDA cases demonstrated a marked increase of parental consanguinity (63%), compared with the general Iranian population (25%) or control cases with tetralogy of Fallot (30%). The recurrence of PDA among siblings was 5%. A genomewide analysis of linkage in 21 unrelated consanguinous PDA cases demonstrated a multipoint logarithm of odds score of 6.27 in favor of linkage of PDA to a 3-centimorgan interval of chromosome 12q24, with 53% of kindreds linked. These findings together establish a recessive component to PDA and implicate a single locus, PDA1, in one third or more of all PDA cases in Iran; they further suggest a role for this locus in PDA worldwide. Finally, these results suggest a general approach to the identification of recessive contributions to sporadic diseases.
authors.affiliation: Department of Medicine and Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Arya
authors.initials: A
authors.lastname: Mani
authors.forename: Seyed-Mahmoud
authors.initials: SM
authors.lastname: Meraji
authors.forename: Roozbeh
authors.initials: R
authors.lastname: Houshyar
authors.forename: Jayaram
authors.initials: J
authors.lastname: Radhakrishnan
authors.forename: Alaleh
authors.initials: A
authors.lastname: Mani
authors.forename: Mehrabeh
authors.initials: M
authors.lastname: Ahangar
authors.forename: Tayebeh M
authors.initials: TM
authors.lastname: Rezaie
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Taghavinejad
authors.forename: Behrooz
authors.initials: B
authors.lastname: Broumand
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D004374:Ductus Arteriosus, Patent / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D005190:Family; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007492:Iran; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D011110:Polymorphism, Genetic