Next generation sequencing is gradually changing the face of human genetic studies. Instead of being largely confined to the analysis of common SNPs shared across many populations and amenable to microarray genotyping, genome-wide studies can now examine a wider range of genetic variants - including more diverse types of variation (such as insertion-deletion polymorphisms), variants specific to particular samples or populations, and rare and low frequency variants. Here, we request continued support for our genetic analysis of aging related traits - with a focus on cardiovascular risk factors - in the isolated population from the island of Sardinia, Italy. Over the next several years, we will use next-generation sequencing technology and high-throughput genotyping to study the relationship between rare genetic variation and key cardiovascular risk factors in a family sample containing ~6,000 individuals (and >30,000 close relative pairs) recruited in the Lanusei valley. As part of our planned experiments, we will evaluate problems related to the selection of samples for sequencing, the design of sequencing experiments and protocols, the analysis and curation of the resulting sequence data, and - finally - association analyses that connect the resulting variants to relevant biomedical traits. Individuals being studies are part of a longitudial study of aging and have been characterized for cardiovascular traits and outcomes, including multiple measurements of key traits such as blood lipid levels and blood pressure. We have previously studied this sample to identify common genetic variants that are associated with these cardiovascular traits and that also contribute to the risk of heart disease and obesity. Our proposed experimental plan presents a unique opportunity to evaluate the role of rare variation in this unique sample. We expect that these studies will result in experimental strategies and analysis tools that will be readily deployable by many laboratories to study the genomes of many other individuals and further our understanding of the genetics and biology of many different traits and conditions.
In the past several years, genome-wide association studies have furthered our understanding of the molecular basis of several traits related to human health and disease. The success of these studies resulted, in large part, from their ability to explore the genome in a comprehensive manner, systematically assessing the impact of common variation on the trait of interest. Here we propose to use a well characterized family sample together with high-throughput sequencing technologies to extend these systematic whole genome assessments to rare variation. Our planned effort complements detailed efforts to characterize common and intermediate frequency genetic variants in the same sample. Our results should expand the understanding of the genetics of cardiovascular traits and also result in strategies that can be widely deployed to study many human traits.
|van den Berg, Marten E; Warren, Helen R; Cabrera, Claudia P et al. (2017) Discovery of novel heart rate-associated loci using the Exome Chip. Hum Mol Genet 26:2346-2363|
|Brody, Jennifer A; Morrison, Alanna C; Bis, Joshua C et al. (2017) Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology. Nat Genet 49:1560-1563|
|McCarthy, Shane; Das, Sayantan; Kretzschmar, Warren et al. (2016) A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet 48:1279-83|
|Ried, Janina S (see original citation for additional authors) (2016) A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. Nat Commun 7:13357|
|Das, Sayantan; Forer, Lukas; Schönherr, Sebastian et al. (2016) Next-generation genotype imputation service and methods. Nat Genet 48:1284-1287|
|Loh, Po-Ru; Danecek, Petr; Palamara, Pier Francesco et al. (2016) Reference-based phasing using the Haplotype Reference Consortium panel. Nat Genet 48:1443-1448|
|Shungin, Dmitry (see original citation for additional authors) (2015) New genetic loci link adipose and insulin biology to body fat distribution. Nature 518:187-196|
|Danjou, Fabrice; Zoledziewska, Magdalena; Sidore, Carlo et al. (2015) Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat Genet 47:1264-71|
|Zoledziewska, Magdalena; Sidore, Carlo; Chiang, Charleston W K et al. (2015) Height-reducing variants and selection for short stature in Sardinia. Nat Genet 47:1352-1356|
|Tan, Adrian; Abecasis, Gonçalo R; Kang, Hyun Min (2015) Unified representation of genetic variants. Bioinformatics 31:2202-4|
Showing the most recent 10 out of 32 publications