Whole Genome Sequence Data Sheds Light on Complex Human Traits.

The architecture of the human genome — its variation, genes and the elements that control them — can define traits that affect a person’s health, including the levels of so-called “good cholesterol,” according to a new study by a consortium of researchers that includes BUSPH biostatistics professor Adrienne Cupples.

In a report online in the journal Nature Genetics, the research team led by the Baylor College of Medicine and the University of Texas Health Science Center at Houston looked at the genome sequences of 962 people to determine the genomic determinants of a trait with many components: high density lipoprotein cholesterol, or HDL-C, which at high levels is believed to protect against heart disease.

The researchers said their study of DNA sequence differences and risk in a large sample of individuals was a milestone that shows that whole genome sequence variation can be analyzed and related to risk of disease. The study is “a precursor to the application of whole genome studies of healthy people, as a part of medical practice,” said Dr. Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center and a senior author of the report.

The consortium found 25 million genetic variants, which they analyzed across regions and with regard to function. They found that common variants explain 61.8 percent of the variance in HDL-C levels, and rare variants explain 7.8 percent. Common variants are variations in a gene that are shared by a significant part of the population. Rare variants occur in only a handful of people.

Through the prism of whole genome sequencing, the researchers found that genetic variation contributed more to HDL-C levels than had been understood from previous studies, known as genome-wide association studies. For example, examining a gene known as CETP showed that variations in regulatory elements were likely to contribute to its role in establishing levels of HDL-C.

The authors wrote: “By using whole-genome sequencing instead of genome-wide association (GWAS) or candidate gene studies, we are able to obtain an unbiased glimpse of the relative contributions of rare and common variation to the heritability of a model trait. The results indicate that the majority (that is, 61.8%) of the heritability of HDL-C levels can be attributable to common variation.”

Besides BUSPH, researchers on the study came from: the University of Washington, Seattle; the National Heart, Lung and Blood Institute Framingham Heart Study; the NHLBI; Kansas State University; the University of North Carolina at Chapel Hill; and the Group Health Research Institute in Seattle.

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