Genome scan of age-at-onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 156B; no. 7; pp. 785 - 798
• Main Authors: Choi, Yoonha, Marchani, Elizabeth E., Bird, Thomas D., Steinbart, Ellen J., Blacker, Deborah, Wijsman, Ellen M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2011; Wiley-Liss
• Subjects: Adult; Adult and adolescent clinical studies; Age; Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease - epidemiology; Alzheimer Disease - genetics; Alzheimer's disease; Apolipoprotein E; Bayes Theorem; Bayesian; Biological and medical sciences; Chromosome 1; chromosome 10; chromosome 19; chromosome 7; Chromosome Mapping; Chromosome Segregation - genetics; Chromosomes, Human - genetics; Classical genetics, quantitative genetics, hybrids; Data processing; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; dementia; Fundamental and applied biological sciences. Psychology; Genetic Heterogeneity; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; genomics; Genotypes; Human; Humans; linkage analysis; Lod Score; MCMC; Medical genetics; Medical sciences; Middle Aged; Models, Genetic; Monte Carlo Method; National Institute of Mental Health (U.S.); Neurodegenerative diseases; Neurology; oligogenic; Organic mental disorders. Neuropsychology; Pedigree; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Quantitative Trait Loci - genetics; Reproducibility of Results; Risk factors; United States - epidemiology; United States; Genetic mapping; Nervous system diseases; Multiple; Alzheimer disease; Pathogenesis; Sample; Bayesian; MCMC; Genetic determinism; Cerebral disorder; oligogenic; Heterogeneity; Age of onset; linkage analysis; Central nervous system disease; Genetic linkage; Genetics; dementia; Degenerative disease; Genome; Locus
• ISSN: 1552-4841; 1552-485X; 1552-485X
• DOI: 10.1002/ajmg.b.31220

Alzheimer's disease (AD) is a common neurodegenerative disorder of late life with a complex genetic basis. Although several genes are known to play a role in rare early onset AD, only the APOE gene is known to have a high contribution to risk of the common late‐onset form of the disease (LOAD, onset >60 years). APOE genotypes vary in their AD risk as well as age‐at‐onset distributions, and it is likely that other loci will similarly affect AD age‐at‐onset. Here we present the first analysis of age‐at‐onset in the NIMH LOAD sample that allows for both a multilocus trait model and genetic heterogeneity among the contributing sites, while at the same time accommodating age censoring, effects of known genetic covariates, and full pedigree and marker information. The results provide evidence for genomic regions not previously implicated in this data set, including regions on chromosomes 7q, 15, and 19p. They also affirm evidence for loci on chromosomes 1q, 6p, 9q, 11, and, of course, the APOE locus on 19q, all of which have been reported previously in the same sample. The analyses failed to find evidence for linkage to chromosome 10 with inclusion of unaffected subjects and extended pedigrees. Several regions implicated in these analyses in the NIMH sample have been previously reported in genome scans of other AD samples. These results, therefore, provide independent confirmation of AD loci in family‐based samples on chromosomes 1q, 7q, 19p, and suggest that further efforts towards identifying the underlying causal loci are warranted. © 2011 Wiley‐Liss, Inc.