title: The MC1R Gene and Youthful Looks.
abstract: Looking young for one's age has been a desire since time immemorial. This desire is attributable to the belief that appearance reflects health and fecundity. Indeed, perceived age predicts survival [1] and associates with molecular markers of aging such as telomere length [2]. Understanding the underlying molecular biology of perceived age is vital for identifying new aging therapies among other purposes, but studies are lacking thus far. As a first attempt, we performed genome-wide association studies (GWASs) of perceived facial age and wrinkling estimated from digital facial images by analyzing over eight million SNPs in 2,693 elderly Dutch Europeans from the Rotterdam Study. The strongest genetic associations with perceived facial age were found for multiple SNPs in the MC1R gene (p < 1 × 10(-7)). This effect was enhanced for a compound heterozygosity marker constructed from four pre-selected functional MC1R SNPs (p = 2.69 × 10(-12)), which was replicated in 599 Dutch Europeans from the Leiden Longevity Study (p = 0.042) and in 1,173 Europeans of the TwinsUK Study (p = 3 × 10(-3)). Individuals carrying the homozygote MC1R risk haplotype looked on average up to 2 years older than non-carriers. This association was independent of age, sex, skin color, and sun damage (wrinkling, pigmented spots) and persisted through different sun-exposure levels. Hence, a role for MC1R in youthful looks independent of its known melanin synthesis function is suggested. Our study uncovers the first genetic evidence explaining why some people look older for their age and provides new leads for further investigating the biological basis of how old or young people look.
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, No.1 Beichen West Road, Chaoyang District, Beijing 100101, China; Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: Merel A
authors.initials: MA
authors.lastname: Hamer
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Unilever R&D, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Japal S
authors.initials: JS
authors.lastname: Lall
authors.affiliation: Department of Dermatology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
authors.affiliation: Unilever R&D, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Murray
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands; Section of Evolutionary Biology, Department of Biology II, Ludwig Maximilians University Munich, Großhaderner Str. 2, 82152 Planegg-Martinsried, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wollstein
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Hae-Won
authors.initials: HW
authors.lastname: Uh
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, No.1 Beichen West Road, Chaoyang District, Beijing 100101, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands; Department of Statistics, School of Mathematics, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.affiliation: Department of Dermatology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: Luba M
authors.initials: LM
authors.lastname: Pardo
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Dermatology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: Tamar
authors.initials: T
authors.lastname: Nijsten
authors.affiliation: Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. Electronic address: m.kayser@erasmusmc.nl.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
authors.affiliation: Unilever R&D, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK. Electronic address: david.gunn@unilever.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Gunn
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D015595:Skin Aging / Q000235:genetics* / Q000502:physiology*
chemical_list: D044102:Receptor, Melanocortin, Type 1
keywords: GWAS; MC1R; age; appearance; facial aging; perceived facial age; skin