Trans-Ethnic Genome-Wide Meta-Analysis of over 9000 Individuals Reveals Multiple Associations with Earlobe Attachment.

ORLOVA, E; LEE MK; ADHIKARI, K; GALLO, C; POLETTI, G; LAVÍNIA SCHULER-FACCINI; BORTOLINI, MARIA CATIRA; CANIZALES-QUINTEROS, S; FRANCISCO ROTHHAMMER; BEDOYA G; GONZÁLEZ JOSÉ, ROLANDO; BALDING D; LESLIE, EJ; FEINGOLD, E; HECHT, J; WHEBY, E; MORENO, LM; DIN, A; TANG, JY; YANG, ; LIN, L; MARAZITA, ML; COX, T; WANG, S; RUIZ-LINARES, A; SCHAFFER, JR; WEINBERG, SM

Vancouver

Congreso; ASHG 2016 Meeting; 2016

The first genome-wide significant associations with the trait were shown in 2015 involving SNPs near the genes EDAR (2q13) and SP5 (2q31), along with a suggestive signal at the 6q24 locus. We performed a meta-analysis of GWAS results from three ethnically distinct cohorts totaling 9155 individuals in an effort to uncover additional genetic signals contributing to variation in earlobe attachment and to investigate whether these signals are population-specific. Earlobe attachment data were available on US individuals of European ancestry (n=1791), a sample of admixed individuals from Latin America (n=4715) and a sample of Han Chinese individuals (n=2649). In each cohort, an ordinal tripartite phenotype definition was used to classify earlobes as free, partially attached, or attached. Results from a common set of 5,366,603 imputed SNPs were meta-analyzed using the inverse variance weighted method in METAL. We observed six genome-wide significant associations: rs3827760 (2q13;p=6.65E-10), rs6756973 (2q31;p=1.40E-28), rs12695694 (3q23;p=4.82E-13), rs58122955 (6q24;p=4.43E-14), rs7096127 (10p12.2;p=2.65E-08), and rs1950357 (14q13;p=4.86E-09). The previously associated signals near EDAR and SP5 were each independently replicated in at least one additional cohort. The previously suggestive signal at 6q24 now reached genome-wide significance. Although there was statistical evidence of effect size heterogeneity at the 3q23 locus (driven primarily by the Chinese cohort), the direction of effect for each of the associated alleles was consistent among cohorts. The associated loci contained several genes involved in morphogenesis. To further investigate these regions, expression of genes in syntenic intervals around the GWAS peaks was investigated in second branchial arch tissue from wildtype E10.5 mouse embryos and two mutants with distinct pinna phenotypes. Of note, Ranbp2 (2q13), Vta1 (6q24), Pax9 (14q13), and Mipol1 (14q13) were highly expressed in wildtype tissue. Sp5 and Gad1, both located at the 2q31 locus, were expressed at relatively low levels in wildtype embryos, but showed evidence of differential expression in the mutants. These findings shed light on the complex genetics underlying variation in ear morphology and highlight the role of several genes in craniofacial morphogenesis.