Journal Article

Genetic identification of a common collagen disease in Puerto Ricans via identity-by-descent mapping in a health system

Kohli, Sumita, Stahl, Eli EA, Young, Kristin L, Gignoux, Christopher R, North, Kari E, Belbin, Gillian Morven, Van Vleck, Tielman, Hindorff, Lucia, Yee, Muh-Ching, Schurmann, Claudia, Cai, Xiaoqiang, Kornreich, Ruth, Cho, Judy H, Abul-Husn, Noura S, Peters, Ulrike, Bottinger, Erwin P, Ruderfer, Douglas, Justice, Anne E, Odgis, Jacqueline, Jeff, Janina M, Merkelson, Amanda, Kenny, Eimear E, James, Regina, Nadkarni, Girish N, Linderman, Michael, Sorokin, Elena P, Graff, Misa, Gottesman, Omri, Wojcik, Genevieve L, Edelmann, Lisa, Glicksberg, Benjamin S, Loos, Ruth JF

2017

Overview

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic Bio Me biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1 , with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease. Diseases often run in families. These disease are frequently linked to changes in DNA that are passed down through generations. Close family members may share these disease-causing mutations; so may distant relatives who inherited the same mutation from a common ancestor long ago. Geneticists use a method called linkage mapping to trace a disease found in multiple members of a family over generations to genetic changes in a shared ancestor. This allows scientists to pinpoint the exact place in the genome the disease-causing mutation occurred. Using computer algorithms, scientists can apply the same technique to identify mutations that distant relatives inherited from a common ancestor. Belbin et al. used this computational technique to identify a mutation that may cause unusually short stature or bone and joint problems in up to 2% of people of Puerto Rican descent. In the experiments, the genomes of about 32,000 New Yorkers who have volunteered to participate in the BioMe Biobank and their health records were used to search for genetic changes linked to extremely short stature. The search revealed that people who inherited two copies of this mutation from their parents were likely to be extremely short or to have bone and joint problems. People who inherited one copy had an increased likelihood of joint or bone problems. This mutation affects a gene responsible for making a form of protein called collagen that is important for bone growth. The analysis suggests the mutation first arose in a Native American ancestor living in Puerto Rico around the time that European colonization began. The mutation had previously been linked to a disorder called Steel syndrome that was thought to be rare. Belbin et al. showed this condition is actually fairly common in people whose ancestors recently came from Puerto Rico, but may often go undiagnosed by their physicians. The experiments emphasize the importance of including diverse populations in genetic studies, as studies of people of predominantly European descent would likely have missed the link between this disease and mutation.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adolescent / Adult / Aged / Child / Collagen / Collagen Diseases - epidemiology / Collagen Diseases - genetics / collagen disorder / Disease / Ecosystems / Electronic Health Records / Epidemiology / Female / Fibrillar Collagens - genetics / Gene mapping / Genetic disorders / Genetics / Genetics and Genomics / Genomes / Genomics / Genotype / GWAS / Haplotypes / Heterozygote / Heterozygotes / Hispanic Americans / Homozygote / Homozygotes / Human Biology and Medicine / Humans / Male / medical genetics / Medical records / Medical research / Medicine / Middle Aged / Molecular Epidemiology / Multigene Family / Musculoskeletal Diseases - epidemiology / Musculoskeletal Diseases - genetics / New York City - epidemiology / New York City - ethnology / Patients / Pedigree / population genetics / Public health / Software / Statistical genetics / Whole Genome Sequencing / Young Adult