Loh Lab

New preprint on large-effect protein-coding repeat polymorphisms

We are excited to share a new preprint, “Protein-coding repeat polymorphisms strongly shape diverse human phenotypes” (Mukamel*, Handsaker* et al.), which finds that some of the largest effects of common genetic variants on human phenotypes arise from variable-number-of-tandem-repeat (VNTR) variation unseen by the analytical approaches used in large-scale human genetic studies. This exciting collaboration with Bob Handsaker and Steve McCarroll leveraged the initial release of N=49,959 UK Biobank exomes to estimate allele lengths (from exome-sequencing depth-of-coverage) for 118 protein-coding VNTRs and impute these alleles into the full UKB cohort (N~500K). Association and fine-mapping analyses showed that VNTRs in five genes (ACANTENT5AMUC1TCHH, and LPA) produce some of the strongest known contributions of any common variants to human traits, including height, serum urea, and hair phenotypes. Moreover, conditioning on VNTR effects in further fine-mapping analyses identified additional coding variants (in three of the five genes) likely to further modify phenotype, including an allelic series of >20 other SNPs in LPA that together with the VNTR explained 90% of lipoprotein(a) variance, enabling further insights into the epidemiological significance of plasma Lp(a) measurements. These results point to strong, cryptic effects of highly polymorphic common structural variants that have largely eluded molecular analyses to date.