Identification of genes promoting skin youthfulness by genome-wide association study

Anne L.S. Chang, Gil Atzmon, Aviv Bergman, Samantha Brugmann, Scott X. Atwood, Howard Y. Chang, Nir Barzilai

Research output: Contribution to journalArticlepeer-review


To identify genes that promote facial skin youthfulness (SY), a genome-wide association study on an Ashkenazi Jewish discovery group (n=428) was performed using Affymetrix 6.0 Single-Nucleotide Polymorphism (SNP) Array. After SNP quality controls, 901,470 SNPs remained for analysis. The eigenstrat method showed no stratification. Cases and controls were identified by global facial skin aging severity including intrinsic and extrinsic parameters. Linear regression adjusted for age and gender, with no significant differences in smoking history, body mass index, menopausal status, or personal or family history of centenarians. Six SNPs met the Bonferroni threshold with P allele <10 -8; two of these six had P genotype <10 -8. Quantitative trait loci mapping confirmed linkage disequilibrium. The six SNPs were interrogated by MassARRAY in a replication group (n=436) with confirmation of rs6975107, an intronic region of KCND2 (potassium voltage-gated channel, Shal-related family member 2) (P genotype =0.023). A second replication group (n=371) confirmed rs318125, downstream of DIAPH2 (diaphanous homolog 2 (Drosophila)) (P allele =0.010, P genotype =0.002) and rs7616661, downstream of EDEM1 (ER degradation enhancer, mannosidase α-like 1) (P genotype =0.042). DIAPH2 has been associated with premature ovarian insufficiency, an aging phenotype in humans. EDEM1 associates with lifespan in animal models, although not humans. KCND2 is expressed in human skin, but has not been associated with aging. These genes represent new candidate genes to study the molecular basis of healthy skin aging.

Original languageEnglish
Pages (from-to)651-657
Number of pages7
JournalJournal of Investigative Dermatology
Issue number3
StatePublished - Mar 2014
Externally publishedYes

Bibliographical note

Funding Information:
We would like to acknowledge Zakia Rahman, MD, Brent Kirkland, MD, and Katherine Arefiev, MD for assistance confirming reproducibility of the global facial skin aging assessment scale used in this study. We are grateful to Lisa Zaba, MD PhD, for expertise in skin immunology and assistance with analyzing skin histology. We thank Wanda Guzman-Delgado, William Greiner, RN, Janet Schein, and Omar Amir, MS, for assistance with data collection and management. We are indebted to Bharathi Lingala, PhD, for statistical consultation and analysis. We also thank Olena Mykhaylichenko for administrative support. This study was funded in part by a Dermatology Foundation Career Development Award (ASC), and by grants from the National Institutes of Health (P01AG021654) (NB), The Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072) (NB), the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation Grant) (NB), and Diabetes Center Grant (DK-20541) (NB). HYC was supported by the Ellison Medical Foundation, Glenn Foundation, and the Howard Hughes Medical Institute Early Career Scientist Award.

ASJC Scopus subject areas

  • Dermatology
  • Molecular Biology
  • Biochemistry
  • Cell Biology


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