Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Some individuals, studies, and centers received individual support. The grant numbers are: Addiction (U01HG004422, NIAAA: U10AA008401, NCI: P01CA089392, NIDA: R01DA013423, R01DA019963); Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (U.S. Public Health Service contracts: N01-CN-45165, N01-RC-45035, N01-RC-37004, NCI contract: HHSN261201000006C); Birth weight (U01HG004415); Blood clotting (R37 HL 039693); Broad Center for Genotyping and Analysis (U01HG04424); Cancer Prevention Study-II (American Cancer Society); Center for Inherited Disease Research (U01HG004438, HHSN268200782096C); Cleft lip/palate (NIDCR: U01DE018993 and R01DE016148, NIH contract: HHSN268200782096C); Dental Caries (NIDCR:U01DE018903 and R01DE014899, NIH CIDR contract: HHSN268200-782096C); Endometrial cancer (R01 CA134958); Fudan Lung Cancer Study (Ministry of Health (201002007); Ministry of Science and Technology (2011BAI09B00); National S&T Major Special Project (2011ZX09102-010-01); China National High-Tech Research and Development Program (2012AA02A517, 2012AA02A518); National Science Foundation of China (30890034); National Basic Research Program (2012CB944600); Scientific and Technological Support Plans from Jiangsu Province (BE2010715)); Gene-Environment Association Studies (Coordinating Center :U01 HG004446, Manuscript preparation: P01-GM099568); Genes and Environment in Lung Cancer, Singapore Study (National Medical Research Council Singapore grant (NMRC/0897/2004, NMRC/1075/2006); Agency for Science, Technology and Research (A*STAR) of Singapore); Genetic Epidemiological Study of Lung Adenocarcinoma (National Research Program on Genomic Medicine in Taiwan (DOH98-TD-G-111-015); National Research Program for Biopharmaceuticals in Taiwan (DOH 100-TD-PB-111-TM013); National Science Council,Taiwan (NSC 100-2319-B-400-001)); Glaucoma (NHGRI: U01HG004728, NEI: R01EY015473, NEI: R01EY015872, Harvard Medical School Distinguished Ophthalmology Scholar Award: Louis Pasquale); Guangdong Study (Foundation of Guangdong Science and Technology Department (2006B60101010, 2007A032000002, 2011A030400010); Guangzhou Science and Information Technology Bureau (2011Y2-00014); Chinese Lung Cancer Research Foundation; National Natural Science Foundation of China (81101549); Natural Science Foundation of Guangdong Province (S2011010000792)); Health Professionals Follow-up Study (UM1 CA167552, R01 HL35464); Hong Kong Study (General Research Fund of Research Grant Council, Hong Kong (781511M)); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Intramural Research Program of the NIH, National Library of Medicine; Intramural Research Program of the National Institute for Occupational Safety and Health; Japanese Female Lung Cancer Collaborative Study (Grants-in-Aid from the Ministry of Health, Labor, and Welfare for Research on Applying Health Technology and for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; National Cancer Center Research and Development Fund; Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and Technology of Japan; NCI (R01-CA121210)); Lung cancer (Z01CP010200); Lung health (U01HG004738); Ministry of Health (201002007); Ministry of Science and Technology (2011BAI09B00); Melanoma (NCI R29CA70334, R01CA100264, P50CA093459); NLCS (China National High-Tech Research and Development Program Grant (2009AA022705); Priority Academic Program Development of Jiangsu Higher Education Institution; National Key Basic Research Program Grant (2011CB503805)); Nurses’ Health Study (P01 CA87969, R01 CA49449); Nurses’ Health Study II (UM1 CA176726, R01, 67262); OpPancreatic cancer (Mayo Clinic SPORE in Pancreatic Cancer: P50CA102701); Prematurity (U01HG004423); Prostate cancer (U01HG004726, NCI: CA63464, CA54281, CA1326792, RC2 CA148085); Shanghai Women’s Health Cohort Study (National Institutes of Health (R37 CA70867); National Cancer Institute intramural research program; NCI Intramural Research Program contract (N02 CP1101066)); Shenyang Lung Cancer Study (National Nature Science Foundation of China (81102194); Liaoning Provincial Department of Education (LS2010168); China Medical Board (00726)); Singapore Chinese Health Study (NIH grants: NCI R01 CA55069, R35 CA53890, R01 CA80205, and R01 CA144034); South Korea Multi-Center Lung Cancer Study (National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0016106); National R&D Program for Cancer Control, Ministry of Health &Welfare, Republic of Korea (0720550-2); (A010250)); Tianjin Lung Cancer Study (Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT); China (IRT1076), Tianjin Cancer Institute and Hospital, National Foundation for Cancer Research US); Venous thromboembolism (U01HG004735); Wuhan lung cancer study (National Key Basic Research and Development Program (2011CB503800)) and Yunnan Lung Cancer Study (Intramural program of U.S. National Institutes of Health; National Cancer Institute). Additionally, K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. The GENEVA consortium thanks the participants and the staff of all GENEVA studies for their important contributions. Support for the GENEVA genome-wide association studies was provided through the NIH Genes, Environment and Health Initiative (GEI).