Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2017 Dec 5

PMID 29198719

Citations 17

Authors

John R Shaffer

Jinxi Li

Myoung Keun Lee

Jasmien Roosenboom

Ekaterina Orlova

Kaustabh Adhikari

Carla Gallo

Giovanni Poletti

Lavinia Schuler-Faccini

Maria-Catira Bortolini

Samuel Canizales-Quinteros

Francisco Rothhammer

Gabriel Bedoya

Rolando Gonzalez-Jose

Paige E Pfeffer

Christopher A Wollenschlaeger

Jacqueline T Hecht

George L Wehby

Lina M Moreno

Anan Ding

Li Jin

Yajun Yang

Jenna C Carlson

Elizabeth J Leslie

Eleanor Feingold

Mary L Marazita

David A Hinds

Timothy C Cox

Sijia Wang

Andres Ruiz-Linares

Seth M Weinberg

Affiliations

Soon will be listed here.

Abstract

The genetic basis of earlobe attachment has been a matter of debate since the early 20 century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic 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 (GPR126), KIAA1217, and PAX9. 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 × 10) loci. 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 results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.

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References

Weinberg S, Raffensperger Z, Kesterke M, Heike C, Cunningham M, Hecht J . The 3D Facial Norms Database: Part 1. A Web-Based Craniofacial Anthropometric and Image Repository for the Clinical and Research Community. Cleft Palate Craniofac J. 2015; 53(6):e185-e197. PMC: 4841760. DOI: 10.1597/15-199. View

Tung J, Do C, Hinds D, Kiefer A, Macpherson J, Chowdry A . Efficient replication of over 180 genetic associations with self-reported medical data. PLoS One. 2011; 6(8):e23473. PMC: 3157390. DOI: 10.1371/journal.pone.0023473. View

Vincent M, Genevieve D, Ostertag A, Marlin S, Lacombe D, Martin-Coignard D . Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet Med. 2015; 18(1):49-56. DOI: 10.1038/gim.2015.29. View

Eppig J, Smith C, Blake J, Ringwald M, Kadin J, Richardson J . Mouse Genome Informatics (MGI): Resources for Mining Mouse Genetic, Genomic, and Biological Data in Support of Primary and Translational Research. Methods Mol Biol. 2016; 1488:47-73. DOI: 10.1007/978-1-4939-6427-7_3. View

Shaffer J, Orlova E, Lee M, Leslie E, Raffensperger Z, Heike C . Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology. PLoS Genet. 2016; 12(8):e1006149. PMC: 4999139. DOI: 10.1371/journal.pgen.1006149. View

Ward L, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2011; 40(Database issue):D930-4. PMC: 3245002. DOI: 10.1093/nar/gkr917. View

Eriksson N, Macpherson J, Tung J, Hon L, Naughton B, Saxonov S . Web-based, participant-driven studies yield novel genetic associations for common traits. PLoS Genet. 2010; 6(6):e1000993. PMC: 2891811. DOI: 10.1371/journal.pgen.1000993. View

Jacques B, Puligilla C, Weichert R, Ferrer-Vaquer A, Hadjantonakis A, Kelley M . A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea. Development. 2012; 139(23):4395-404. PMC: 3509733. DOI: 10.1242/dev.080358. View

Fujimoto A, Kimura R, Ohashi J, Omi K, Yuliwulandari R, Batubara L . A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness. Hum Mol Genet. 2007; 17(6):835-43. DOI: 10.1093/hmg/ddm355. View

10.

Lausch E, Hermanns P, Farin H, Alanay Y, Unger S, Nikkel S . TBX15 mutations cause craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature in Cousin syndrome. Am J Hum Genet. 2008; 83(5):649-55. PMC: 2668032. DOI: 10.1016/j.ajhg.2008.10.011. View

11.

Birnbaum S, Reutter H, Mende M, de Assis N, Diaz-Lacava A, Herms S . Further evidence for the involvement of MYH9 in the etiology of non-syndromic cleft lip with or without cleft palate. Eur J Oral Sci. 2009; 117(2):200-3. DOI: 10.1111/j.1600-0722.2008.00604.x. View

12.

Lai L, Walsh R . Observations on ear lobe types. Acta Genet Stat Med. 1966; 16(3):250-7. DOI: 10.1159/000151971. View

13.

Hellingman C, Verwiel E, Slagt I, Koevoet W, Poublon R, Nolst-Trenite G . Differences in cartilage-forming capacity of expanded human chondrocytes from ear and nose and their gene expression profiles. Cell Transplant. 2010; 20(6):925-40. DOI: 10.3727/096368910X539119. View

14.

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

15.

Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren M . Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5):511-5. PMC: 3146043. DOI: 10.1038/nbt.1621. View

16.

Tan J, Yang Y, Tang K, Sabeti P, Jin L, Wang S . The adaptive variant EDARV370A is associated with straight hair in East Asians. Hum Genet. 2013; 132(10):1187-91. DOI: 10.1007/s00439-013-1324-1. View

17.

Bryk J, Hardouin E, Pugach I, Hughes D, Strotmann R, Stoneking M . Positive selection in East Asians for an EDAR allele that enhances NF-kappaB activation. PLoS One. 2008; 3(5):e2209. PMC: 2374902. DOI: 10.1371/journal.pone.0002209. View

18.

Smits P, Saada A, Wortmann S, Heister A, Brink M, Pfundt R . Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy. Eur J Hum Genet. 2010; 19(4):394-9. PMC: 3060326. DOI: 10.1038/ejhg.2010.214. View

19.

Tan J, Peng Q, Li J, Guan Y, Zhang L, Jiao Y . Characteristics of dental morphology in the Xinjiang Uyghurs and correlation with the EDARV370A variant. Sci China Life Sci. 2014; 57(5):510-8. DOI: 10.1007/s11427-014-4654-x. View

20.

Patra C, van Amerongen M, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T . Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent. Proc Natl Acad Sci U S A. 2013; 110(42):16898-903. PMC: 3801000. DOI: 10.1073/pnas.1304837110. View