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Hum Genet. 2019 Mar;138(3):271-285. doi: 10.1007/s00439-019-01988-9. Epub 2019 Feb 25.

Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis.

Zhu Z1,2, Lin Y1, Li X3, Driver JA4,5, Liang L6,7.

Author information

1
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
2
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
3
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
4
Geriatric Research Education and Clinical Center and Massachusetts Veterans Epidemiology Research and Information Center, VA Medical Center, Boston, MA, USA.
5
Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. lliang@hsph.harvard.edu.
7
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. lliang@hsph.harvard.edu.

Abstract

A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer's disease (AD), especially glucose-related dysfunction; one hypothesis for this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Local genetic covariance analysis found that 19q13 region had strong local genetic correlation between AD and T2D (P = 6.78 × 10- 22), LDL (P = 1.74 × 10- 253) and HDL (P = 7.94 × 10- 18). Cross-trait meta-analysis identified 4 loci that were associated with AD and fasting glucose, 3 loci that were associated with AD and fasting insulin, and 20 loci that were associated with AD and HDL (Pmeta < 1.6 × 10- 8, single trait P < 0.05). Functional analysis revealed that the shared genes are enriched in amyloid metabolic process, lipoprotein remodeling and other related biological pathways; also in pancreas, liver, blood and other tissues. Our work identifies common genetic architectures shared between AD and fasting glucose, fasting insulin and HDL, and sheds light on molecular mechanisms underlying the association between metabolic dysregulation and AD.

PMID:
30805717
DOI:
10.1007/s00439-019-01988-9
[Indexed for MEDLINE]

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