title: Genome-wide association analysis of secondary imaging phenotypes from the Alzheimer's disease neuroimaging initiative study.
abstract: The aim of this paper is to systematically evaluate a biased sampling issue associated with genome-wide association analysis (GWAS) of imaging phenotypes for most imaging genetic studies, including the Alzheimer's Disease Neuroimaging Initiative (ADNI). Specifically, the original sampling scheme of these imaging genetic studies is primarily the retrospective case-control design, whereas most existing statistical analyses of these studies ignore such sampling scheme by directly correlating imaging phenotypes (called the secondary traits) with genotype. Although it has been well documented in genetic epidemiology that ignoring the case-control sampling scheme can produce highly biased estimates, and subsequently lead to misleading results and suspicious associations, such findings are not well documented in imaging genetics. We use extensive simulations and a large-scale imaging genetic data analysis of the Alzheimer's Disease Neuroimaging Initiative (ADNI) data to evaluate the effects of the case-control sampling scheme on GWAS results based on some standard statistical methods, such as linear regression methods, while comparing it with several advanced statistical methods that appropriately adjust for the case-control sampling scheme.
authors.affiliation: School of Mathematics & Statistics and KLAS, Northeast Normal University, Changchun 130024, China; Departments of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Takeda Pharmaceuticals U.S.A., Inc., 300 Massachusetts Ave, Cambridge, MA 02139, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Departments of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Departments of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Departments of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Knickmeyer
authors.affiliation: Departments of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: hzhu5@mdanderson.org.
authors.forename: Hongtu
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D016022:Case-Control Studies; D003198:Computer Simulation; D005260:Female; D055106:Genome-Wide Association Study / Q000592:standards*; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000592:standards; D008297:Male; D059906:Neuroimaging / Q000592:standards*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012107:Research Design / Q000592:standards*
keywords: Alzheimer's Disease Neuroimaging Initiative; Case-control; Genome-wide association analysis; Imaging genetics; Secondary trait