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Admixture mapping identifies a locus at 15q21.2–22.3 associated with keloid formation in African Americans

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Abstract

Keloids are benign dermal tumors that occur ~20 times more often in African versus Caucasian descent individuals. While most keloids occur sporadically, a genetic predisposition is supported by both familial aggregation of some keloids and the large differences in risk among populations. Yet, no well-established genetic risk factors for keloids have been identified. In this study, we conducted admixture mapping and whole-exome association using 478 African Americans (AAs) samples (122 cases, 356 controls) with exome genotyping data to identify regions where local ancestry associated with keloid risk. Logistic regression was used to evaluate associations under admixture peaks. A significant mapping peak was observed on chr15q21.2–22.3. This peak included NEDD4, a gene previously implicated in a keloid genome-wide association study (GWAS) of Japanese individuals later validated in a Chinese cohort. While we observed modest evidence for association with NEDD4, a more significant association was observed at (myosin 1E) MYO1E. A genome scan not including the 15q21-22 region also identified associations at MYO7A (rs35641839, odds ratio [OR] = 4.71, 95 % confidence interval [CI] 2.38–9.32, p = 8.34 × 10−6) at 11q13.5. The identification of SNPs in two myosin genes strongly associated with keloid formation suggests that an altered cytoskeleton contributes to the enhanced migratory and invasive properties of keloid fibroblasts. Our findings support the admixture mapping approach for the study of keloid risk, and indicate potentially common genetic elements on chr15q21.2–22.3 in causation of keloids in AAs, Japanese, and Chinese populations.

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Acknowledgments

This work was supported by NIH Grants F33AR052241 (SBR), P50DE10595 (SBR), R03AR048938 (SMW), P30AR041943 (SMW), P20GM103534 (SMW), pilot Grant from the Center for Human Genetics Research at VU (SBR, DRVE and TLE), 1UL1RR024975 (SBR), 5KL2TR000446-08 (TLE), 5K12HD04383-12 (DRVE) and by resources of Vanderbilt University School of Medicine and University of North Carolina Functional Genomics Core. The Project described was also supported by CTSA award No. UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the NIH.

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None declared.

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Authors and Affiliations

  1. Vanderbilt Epidemiology Center, 2525 West End Ave., Suite 600 6th Floor, Nashville, TN, 37203, USA

    Digna R. Velez Edwards & Todd L. Edwards

  2. Institute for Medicine and Public Health, Nashville, USA

    Digna R. Velez Edwards & Todd L. Edwards

  3. Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    Digna R. Velez Edwards, Krystal S. Tsosie, Todd L. Edwards & Shirley B. Russell

  4. Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA

    Digna R. Velez Edwards

  5. Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, TN, USA

    Krystal S. Tsosie & Todd L. Edwards

  6. Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA

    Scott M. Williams

  7. Division of Dermatology, Department of Medicine, Vanderbilt University, Nashville, TN, USA

    Shirley B. Russell

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  1. Digna R. Velez Edwards
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Correspondence to Digna R. Velez Edwards or Todd L. Edwards.

Additional information

D. R. Velez Edwards and K. S. Tsosie are co-first author equal contribution.

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Supplemental Fig. 1. Quality control flow chart

Supplemental Fig. 2. Quantile–quantile (Q–Q) plot of LAMP analyses. Expected −log10 p values are on the x-axis and the observed −log10 p values are on the y-axis.

Supplemental Fig. 3. Multidimensional scaling plots of keloid cases and controls with HapMap populations. MDS axes for AAs were plotted with MDS1 on the y-axis and MDS2 on the x-axis. Values were color coded according to self-reported race (AA light blue circles keloid cases, AA dark blue circles controls, AA HapMap reference population (ASW) black circles, European American HapMap reference population (CEU) red circles, and African HapMap reference population (YRI) green circles).

Supplemental Fig. 4. Summary of strongest admixture mapping peaks across all chromosomes. X-axis indicates genomic position along the chromosome. Y-axis indicates −log10 (p value) from logistic regression (adjusted for sex and top 10 PCs) of admixture mapping values generated from LAMP. Dotted line indicates threshold of significance, as determined by negative log value of the family-wise error rate (FWER), calculated from n = 1,000 permutations in multiple testing (top line), the bottom line is an arbitrary threshold that is one log down from the FWER.

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Velez Edwards, D.R., Tsosie, K.S., Williams, S.M. et al. Admixture mapping identifies a locus at 15q21.2–22.3 associated with keloid formation in African Americans. Hum Genet 133, 1513–1523 (2014). https://doi.org/10.1007/s00439-014-1490-9

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  • DOI: https://doi.org/10.1007/s00439-014-1490-9

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