title: Heritability of magnetic resonance imaging (MRI) traits in Alzheimer disease cases and their siblings in the MIRAGE study.
abstract: Magnetic resonance imaging (MRI) traits can serve as more specific measures of degenerative or cerebrovascular brain injury than can be ascertained through personal history, risk factors, clinical signs, or symptoms. They are potentially useful intermediate phenotypes for genetic studies of Alzheimer disease (AD). Recent studies have estimated heritability of white matter hyperintensity (WMH) among cognitively normal family members to be between 0.55 and 0.73. Persons discordant for AD are expected to have substantially different MRI phenotype distributions; our goal was to determine whether MRI traits in siblings discordant for AD are heritable. We measured cerebral atrophy, medial temporal atrophy (MTA), WMH, and a rating of cerebrovascular disease (CVR) via MRI in 815 participants from 424 families of the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study. Residual heritability after adjustment for covariates ranged from 0.17 (P=0.009) for MTA to 0.57 (P=10(-7)) for CVR. The number of APOE-epsilon4 alleles was significantly associated with WMH (P=0.01) and CVR (P=0.005) but not cerebral atrophy (P=0.25) or MTA (P=0.83). Heritability remained significant and high after adjusting for APOE genotype, suggesting that a substantial proportion of the additive genetic variation in these MRI traits is explained by other genes. In the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study of AD-discordant siblings, MRI traits are heritable and are potential endophenotypes for genetic association studies.
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. klunetta@bu.edu
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Porat M
authors.initials: PM
authors.lastname: Erlich
authors.forename: Karen T
authors.initials: KT
authors.lastname: Cuenco
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Charles
authors.initials: C
authors.lastname: Decarli
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010375:Pedigree; D019655:Quantitative Trait, Heritable; D035781:Siblings
chemical_list: D053327:Apolipoprotein E4