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UK Biobank Exome Study Uncovers Rare Variants Contributing to Cardiometabolic Disease, Traits

NEW YORK – An international team led by investigators at the Broad Institute, the University of Amsterdam, and Massachusetts General Hospital has identified dozens of rare variants associated with cardiometabolic traits or conditions ranging from height to blood lipid profiles and type 2 diabetes.

"[L]arge-scale sequencing has enabled the dissection of the rare genetic contributors to cardiometabolic traits and diseases," senior and co-corresponding author Patrick Ellinor, a cardiovascular disease researcher at the Broad and Massachusetts General Hospital, and his colleagues wrote, adding that "our findings may facilitate studies aimed at therapeutics and screening of cardiovascular and metabolic disorders."

For a study published in Nature Genetics on Thursday, the researchers looked at data from more than 200,300 comprehensively phenotyped UK Biobank participants who had undergone exome sequencing. When they searched for rare variants coinciding with more than 80 cardiovascular, metabolic, or anthropometric traits or conditions, they unearthed associations involving variants in 57 genes, including 42 known associations and 15 that had not been reported in the past.

The team confirmed associations at 13 of the newly detected cardiometabolic risk loci in another 166,000 exome-sequenced individuals from the Geisinger MyCode cohort who also had electronic health record data available.

The researchers also investigated ties between Mendelian disease genes, common genetic risk variants, and the rare variants identified in the UK Biobank participants, shoring up several proposed associations.

"There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1, and TTN," the authors reported, noting that "[m]any genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes."

Based on findings from the exome sequencing analysis, the team estimated that rare risk variants linked to cardiovascular or metabolic conditions are likely present in at least 1 percent and as many as 2.4 percent of the 200,337 UK Biobank participants profiled for the study.

Depending on the stringency used to select the cardiometabolic risk genes included in their analyses, the investigators found potentially pathogenic variants in between 2,098 and nearly 4,900 of the individuals in the cohort.

They cautioned that the findings may not extend directly to other populations, since the UK Biobank group is skewed toward middle-aged European individuals and relies, in some cases, on self-reported traits or diagnoses. Even so, they suggested that the new findings "have several analytical implications for rare variant analysis in large biobanks," and argued that "UK Biobank analyses using data from all 500,000 samples may prove particularly fruitful for complex diseases in the future."