Murray Brilliant, PhD

Brilliant Slide of the Week

Title: Genetics of Height

Legend:  Effect size vs. allele frequency of 606 height variants with P<2×10-7. Variants with larger effect sizes on height variations tend to be rarer. We observed an inverse relationship between the effect size (from the combined “discovery+validation” analysis, in cm on the y-axis) and the minor allele frequency (MAF) for the height variants (x-axis, from 0 to 50%).

Citation: Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR et al. (2017). Rare and low-frequency coding variants alter human adult height. Nature. 2017 Feb 9;542(7640):186-190. doi: 10.1038/nature21039. Epub 2017 Feb 1.  PMID: 28146470

Abstract: Height is a highly heritable, classic polygenic trait with approximately 700 commonly associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), which is greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes and that these variants implicate relevant genes and pathways.

About the Lab: Research in the Brilliant laboratory focuses on understanding the genetics of Mendelian (single-gene) traits and complex (multigene) traits. Disorders studied include albinism, fragile X syndrome, Rett syndrome, hereditary hemorrhagic telangiectasia, and ALS.  Complex traits include normal human pigmentation, height and other traits, as well as genetically complex diseases such as age-related macular degeneration, glaucoma and coronary disease. Discovery efforts are aided by the Personalized Medicine Research Project that links DNA variants and medical diagnoses of 20,000 volunteers. Research extends to designing and evaluating best practices to  implement our research findings into improved clinical care, beginning with precision medicine efforts to reduce adverse drug reactions.

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