Multi-ethnic genome-wide association study (GWAS) reveals polygenic architecture of earlobe attachment

I can still remember the day when one of my sons (and he was certainly no more than 6 years old) was deep in thought and then asked, “How many genes do you think it would take to make a jaw?” After picking myself up off the floor, I began explaining to him that “to form any facial features” must take a large number of contributing genes (but I didn’t go into defining “multifactorial trait” for him at that time). Earlobe attachment is another “facial features” trait (phenotype) that helps to define the appearance of each individual, and clearly (if one has sat on a bus in New York City or London, and noticed different ethnic groups) the trait seems to be linked to other aspects of ethnic facial features.

As early as 1937, a geneticist [J Hered 1937; 28: 425-236] had pointed out that earlobe attachment is likely to be “a polygenic trait” (i.e. phenotype reflected by the contribution of multiple, or many, genes) “exhibiting a continuous phenotypic distribution.” Although earlobe attachment is a neutral morphological trait (i.e. no apparent survival or reproductive advantage) –– understanding its genetic etiology is valuable in that it offers a glimpse into the biological basis of ear development, improving our understanding of genes potentially involved in developmental (birth) defects. Moreover, it serves as an instructive example of simple versus polygenic inheritance in an accessible, easy-to-observe-and-measure trait.

Recent genome-wide association studies (GWASs) have investigated earlobe attachment and reported significant associations with variants in the EDAR and SP5 genes. However, these (and other suggested associations with specific genetic loci) have yet to be replicated in independent additional studies. Of note, ethnic differences in the frequency of earlobe attachment are well documented, suggesting that genetic heterogeneity might underlie the trait and that deciphering its genetic architecture might require studies across numerous ethnic groups. This notion is supported by the fact that one of the two previously reported associations was with a missense EDAR variant (i.e. DNA base change that alters an amino acid) that is common in Asian and Amerindian populations but absent or infrequent in European and African populations.

Authors [see attached article] performed a GWAS of earlobe attachment in a multi-ethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater, and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes –– including EDAR, SP5, MRPS22, ADGRG6, KIAA1217, and PAX9. These genes and their functions can be searched for on the web site.) The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (P <5.0 x 10–8) loci. Intriguingly, annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA-sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These exciting results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development. Am J Hum Genet 7 Dec 2o17; 101: 913–924

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