Single-nucleotide polymorphisms in the COL1A1 regulatory regions are associated with otosclerosis.

Otosclerosis (MIM 166800) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this ethnic group. Although measles virus, hormones, human leukocyte antigen alleles and genetic factors have been implicated in the development of otosclerosis, its etiology remains unknown. In a focused effort to identify genetic factors in otosclerosis, we have mapped four disease loci (MIM 166800/605727/608244/608787); however, cloning the disease-causing genes in these intervals has not been successful. Here, we used a case-control study design to investigate the association between collagen type I genes and otosclerosis. We identified susceptibility and protective haplotypes in COL1A1 that are significantly associated with otosclerosis in the Caucasian population. These haplotypes alter reporter gene activity in an osteoblast cell line by affecting binding of transcription factors to cis-acting elements. Our data suggest that increased amounts of collagen alpha1(I) homotrimers are causally related to the development of otosclerosis. Consistent with this hypothesis, mouse mutants homozygous for a Col1a2 frameshift mutation on a C57BL/6J background that deposit only homotrimeric type I collagen have hearing loss.

Strategies for identification of disease genes.

Many genetic disorders are caused by mutations in single genes (monogenic diseases), and the inheritance pattern of these diseases follows simple rules. If a mutation in both copies of the gene on both chromosome homologues is necessary to cause the disease, the inheritance pattern is recessive, and a patient is the offspring of two clinically unaffected carriers. However, if a mutation in a single homologue is sufficient, the inheritance pattern is dominant and the disease is transmitted from generation to generation. Monogenic diseases are responsible for only a small fraction of all patients with genetic diseases. Many common diseases, including cancer, heart disease, diabetes and several psychiatric diseases, are the results of a complex interaction between genetic and environmental factors. However, these diseases can have important genetic components and can therefore still be considered genetic diseases. The identification of genes involved in complex genetic diseases can be very important for the understanding and treatment of these diseases. Over the last 15 years, much progress has been made in the identification of genes responsible for monogenic diseases, but the identification of genes involved in complex diseases has been more difficult, and at this moment little is known about the genes involved in most common diseases.