title: Pigmentation-Independent Susceptibility Loci for Actinic Keratosis Highlighted by Compound Heterozygosity Analysis.
abstract: Actinic keratosis (AK) is a skin disease frequently found in European elderly, and it represents the precursor of cutaneous squamous cell carcinoma. Our recent genome-wide association study highlighted DNA variants in two pigmentation genes, IRF4 and MC1R, that confer AK risk in Europeans. Here, we performed a genome-wide search for relaxed forms of compound heterozygosity in association with AK using our recently developed software CollapsABEL. In a discovery dataset of 3,193 Dutch Europeans, a total of 15 genetic loci showed genome-wide significant association with AK (P < 1.25 × 10-10). Of those, three loci (6p21.2, 6p12.2, and 6q13) were confirmed in a replication dataset that included 624 additional Dutch Europeans (P < 0.05). These replicated loci harbored six genes (KCNK5/KCNK17, PAQR8/GSTA2, and KCNQ5/KHDC1), none of them known to be involved in pigmentation. A candidate compound heterozygosity analysis for 12 pigmentation loci highlighted SLC24A4 at 14q32.12 as showing significant association with AK (P = 8.83 × 10-9). The four significantly AK-associated compound heterozygosity single-nucleotide polymorphism pairs together explained 4.37% of the total AK variation, which was 2.62 times greater than the two top-associated individual single nucleotide polymorphisms together (1.67%) identified in the previous conventional genome-wide association study. In conclusion, CollapsABEL showed compound heterozygosity in non-pigmentation- and pigmentation-related loci conferring genetic risk of AK.
authors.affiliation: Department of Genetic Identification, Erasmus Medical Center University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Kaiyin
authors.initials: K
authors.lastname: Zhong
authors.affiliation: Department of Dermatology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Joris A C
authors.initials: JAC
authors.lastname: Verkouteren
authors.affiliation: Department of Dermatology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Leonie C
authors.initials: LC
authors.lastname: Jacobs
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Genetic Identification, Erasmus Medical Center University Medical Center Rotterdam, Rotterdam, The Netherlands; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands. Electronic address: t.nijsten@erasmusmc.nl.
authors.forename: Tamar
authors.initials: T
authors.lastname: Nijsten
authors.affiliation: Department of Genetic Identification, Erasmus Medical Center University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: m.kayser@erasmusmc.nl.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D016208:Databases, Factual; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D055623:Keratosis, Actinic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D012880:Skin Pigmentation / Q000235:genetics; D044465:White People / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4