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. 2002 Nov 12;99(23):15054-9.
doi: 10.1073/pnas.192582999. Epub 2002 Oct 30.

Finding genetic contributions to sporadic disease: a recessive locus at 12q24 commonly contributes to patent ductus arteriosus

Arya Mani  1 , Seyed-Mahmoud Meraji, Roozbeh Houshyar, Jayaram Radhakrishnan, Alaleh Mani, Mehrabeh Ahangar, Tayebeh M Rezaie, Mohammad-Ali Taghavinejad, Behrooz Broumand, Hongyu Zhao, Carol Nelson-Williams, Richard P Lifton
Affiliations

Finding genetic contributions to sporadic disease: a recessive locus at 12q24 commonly contributes to patent ductus arteriosus

Arya Mani et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Fig 1.
Fig 1.
Cross-section of term PDA. A segment of a term PDA was obtained after therapeutic surgical ligation and resection. A Van Giessen stain is shown. The lumen is widely patent. The internal elastic lamina (lamina interna, LI) is disrupted (arrow), as occurs in the normal closure of the ductus; however, few smooth muscle cells have migrated into the intima (I), and intimal cushions have not formed. M, vessel media.
Fig 2.
Fig 2.
Genotypes at 12q24 in PDA kindreds. Genotypes of 36 marker loci at 12q24 are shown for nine consanguinous PDA kindreds that show evidence of linkage. At the top, each kindred number is shown, followed by the parental relationship (1st denotes first cousins, etc.), followed by the multipoint lod score at the position of locus D12S395. Genotypes of 36 marker loci spanning a 51-cM interval of 12q24 are shown in their chromosomal order for each affected individual; the positions of each marker on the genetic and physical maps are indicated in cM and Mb, respectively. Homozygous chromosome segments within the linked interval are enclosed in boxes.
Fig 3.
Fig 3.
Multipoint analysis of linkage of PDA to 12q24. The multipoint lod score for linkage of PDA across a 60-cM segment of chromosome 12 for all 21 kindreds is shown. The positions of 36 marker loci are shown at the top, and the multipoint lod scores calculated by using homozygosity mapping with the GENEHUNTER program are shown. The lod score peak occurs at zero recombination with marker D12S1721. The lod-1 interval for the location of PDA1 is represented as a thick bar. PAH, a tetranucleotide repeat STS in intron 3 of the phenylalanine hydroxylase gene.
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