Journal Article

Consanguinity Mapping of Congenital Heart Disease in a South Indian Population

Friedman, Richard D., Sexton, David, Orabona, Guilherme, Maheshwari, Sunita, Bartlett, Jackie, McGregor, Tracy L., Misri, Amit, Morgan, Thomas M.

2010

Overview

Parental consanguinity is a risk factor for congenital heart disease (CHD) worldwide, suggesting that a recessive inheritance model may contribute substantially to CHD. In Bangalore, India, uncle-niece and first cousin marriages are common, presenting the opportunity for an international study involving consanguinity mapping of structural CHD. We sought to explore the recessive model of CHD by conducting a genome-wide linkage analysis utilizing high-density oligonucleotide microarrays and enrolling 83 CHD probands born to unaffected consanguineous parents. In this linkage scan involving single nucleotide polymorphism (SNP) markers, the threshold for genome-wide statistical significance was set at the standard log-of-odds (LOD) score threshold of 3.3, corresponding to 1995ratio1 odds in favor of linkage. We identified a maximal single-point LOD score of 3.76 (5754ratio1 odds) implicating linkage of CHD with the major allele (G) of rs1055061 on chromosome 14 in the HOMEZ gene, a ubiquitously expressed transcription factor containing leucine zipper as well as zinc finger motifs. Re-sequencing of HOMEZ exons did not reveal causative mutations in Indian probands. In addition, genotyping of the linked allele (G) in 325 U.S. CHD cases revealed neither genotypic nor allele frequency differences in varied CHD cases compared to 605 non-CHD controls. Despite the statistical power of the consanguinity mapping approach, no single gene of major effect could be convincingly identified in a clinically heterogeneous sample of Indian CHD cases born to consanguineous parents. However, we are unable to exclude the possibility that noncoding regions of HOMEZ may harbor recessive mutations leading to CHD in the Indian population. Further research involving large multinational cohorts of patients with specific subtypes of CHD is needed to attempt replication of the observed linkage peak on chromosome 14. In addition, we anticipate that a targeted re-sequencing approach may complement linkage analysis in future studies of recessive mutation detection in CHD.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acute coronary syndromes / Alleles / Analysis / Autism / Biophysics / Cardiovascular disease / Cardiovascular diseases / Children & youth / Chromosome 14 / Chromosomes, Human, Pair 14 / Clinical trials / Congenital diseases / Congenital heart defects / Consanguinity / Coronary artery disease / DNA binding proteins / DNA microarrays / Exons / Families & family life / Gene frequency / Gene mapping / Genes, Recessive / Genetic aspects / Genetic disorders / Genetic Linkage / Genetic Predisposition to Disease / Genetics / Genetics and Genomics/Complex Traits / Genetics and Genomics/Gene Discovery / Genetics and Genomics/Genetics of Disease / Genetics and Genomics/Medical Genetics / Genome, Human / Genome-Wide Association Study - methods / Genomes / Genomics / Genotyping / Health risk assessment / Health risks / Heart Defects, Congenital - genetics / Heart diseases / Heart surgery / Heredity / Homeodomain Proteins - genetics / Hospitals / Humans / India - epidemiology / International studies / Leucine / Leucine zipper proteins / Linkage analysis / Lod Score / Mapping / Medicine / Mutation / National libraries / Nuclear electric power generation / Oligonucleotides / Parents / Parents & parenting / Patients / Pediatrics / Physiology / Polymorphism / Population / Population (statistical) / Pulmonary hypertension / Risk factors / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Statistics / Transcription (Genetics) / Transcription Factors - genetics / Zinc / Zinc finger proteins