Identification of genetic heterogeneity of Alzheimer's disease across age

Min-Tzu Lo; Karolina Kauppi; Chun-Chieh Fan; Nilotpal Sanyal; Emilie T Reas; V S Sundar; Wen-Chung Lee; Rahul S Desikan; Linda K McEvoy; Chi-Hua Chen; Alzheimer's Disease Genetics Consortium

doi:10.1016/j.neurobiolaging.2019.02.022

Identification of genetic heterogeneity of Alzheimer's disease across age

Neurobiol Aging. 2019 Dec:84:243.e1-243.e9. doi: 10.1016/j.neurobiolaging.2019.02.022. Epub 2019 Mar 12.

Authors

Affiliations

¹ Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, CA, USA; Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA, USA. Electronic address: lomintzu@gmail.com.
² Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, CA, USA; Department of Radiation Sciences, Umea University, Umea, Sweden.
³ Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, CA, USA; Department of Cognitive Science, University of California, San Diego, CA, USA.
⁴ Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, CA, USA.
⁵ Department of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁶ Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
⁷ Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, CA, USA. Electronic address: chc101@ucsd.edu.

PMID: 30979435
PMCID: PMC6783343
DOI: 10.1016/j.neurobiolaging.2019.02.022

Abstract

The risk of APOE for Alzheimer's disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity of AD and identify genomic loci with differential effects across age. Stratified gene-based genome-wide association studies and polygenic variation analyses were performed in the younger (60-79 years, N = 14,895) and older (≥80 years, N = 6559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (r_g = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (p < 0.05). APOE region, BIN1, OR2S2, MS4A4E, and PICALM were identified at the gene-based genome-wide significance (p < 2.73 × 10^-6) with larger effects at younger age (except MS4A4E). For the novel gene OR2S2, we further performed leave-one-out analyses, which showed consistent effects across subsamples. Our results suggest using genetically more homogeneous individuals may help detect additional susceptible loci.

Keywords: Alzheimer's disease; Gene-based analysis; Genetic correlation; Genetic heterogeneity; Stratified GWAS.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics*
Genetic Heterogeneity*
Humans

Abstract

Publication types

MeSH terms

Grants and funding