title: Gene-based rare allele analysis identified a risk gene of Alzheimer's disease.
abstract: Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P<1.8×10(-6) (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ε4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies.
authors.affiliation: Department of Neurology, Dementia Center, Stroke Center, Ilsan hospital, National Health Insurance Service, Goyang-shi, South Korea.
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Neurology, Inje University Ilsan Paik Hospital, Goyang-shi, South Korea.
authors.forename: Pamela
authors.initials: P
authors.lastname: Song
authors.affiliation: Clinical Research Management Team, Ilsan hospital, National Health Insurance Service, Goyang-shi, South Korea.
authors.forename: Hyunsun
authors.initials: H
authors.lastname: Lim
authors.affiliation: Department of Life and Nanopharmaceutical Sciences and Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul, South Korea.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Neurology, Dementia Center, Stroke Center, Ilsan hospital, National Health Insurance Service, Goyang-shi, South Korea.
authors.forename: Jun Hong
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon-shi, South Korea.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Park
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D015201:Meta-Analysis as Topic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide