RESUMO
We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10-12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10-18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.
Assuntos
Proteína de Matriz Oligomérica de Cartilagem/genética , Proteínas da Matriz Extracelular/genética , Predisposição Genética para Doença/genética , Genoma Humano/genética , Osteoartrite do Quadril/genética , Análise de Sequência de DNA/métodos , Artroplastia de Quadril , Células Cultivadas , Códon sem Sentido , Mutação da Fase de Leitura , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Islândia , Estimativa de Kaplan-Meier , Mutação de Sentido Incorreto , Osteoartrite do Quadril/cirurgia , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
Eight regions of the genome (PARK1-8) have been implicated in autosomal dominant and autosomal recessive forms of early-onset Parkinson's disease. These forms constitute a few of all cases. However, except for a haplotype in six families (PARK3), no study has successfully mapped a gene or described mutations that contribute to the common late-onset Parkinson's disease. Some have even suggested that a genetic component does not exist. We cross-matched our nationwide genealogy database with a population-based list of Icelandic Parkinson's disease patients to search for families with more than one patient. We performed a genomewide scan on 117 patients and 168 of their unaffected relatives within 51 families using 781 microsatellite markers. Allele-sharing, model-independent analysis of the results showed linkage to a region on chromosome 1p32 with a logarithm of odds score of 3.9 (Z(lr) = 4.2). By increasing the information content with additional microsatellite markers in this region, we found that the logarithm of odds score increased to 4.9 (Z(lr) = 4.8). This result corresponds to an unadjusted p value of 1.0 x 10(-6) and p < 0.005 after adjusting for a genomewide search. We designate this region PARK10. We therefore have successfully mapped, to genomewide significance, a susceptibility gene for late-onset Parkinson's disease using multiple families drawn across a whole population. Identification of the susceptibility gene in this region may pave the way for a better understanding of the disease process, which, in turn, may lead to improved diagnostics and therapeutics.