한빛사논문
- 조회570
Hyunwoong Ko,1,2,3,† Soyeon Kim,4,5,6,† Kiwon Kim,7 Sang-Hyuk Jung,4 Injeong Shim,4 Soojin Cha,4 Hyewon Lee,8 Beomsu Kim,4 Joohyun Yoon,9 Tae Hyon Ha,9 Seyul Kwak,2 Jae Myeong Kang,10 Jun-Young Lee,2 Jinho Kim,11 Woong-Yang Park,12 Kwangsik Nho,13 Doh Kwan Kim,14 Woojae Myung9,‡ and Hong-Hee Won4,12,‡
1Interdisciplinary Program in Cognitive Science, Seoul National University, Seoul, South Korea
2Department of Psychiatry, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
3Dental Research Institute, Seoul National University School of Dentistry, Seoul, South Korea
4Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea
5Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
6Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7Department of Psychiatry, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
8Department of Health Administration and Management, College of Medical Sciences, Soonchunhyang University, Asan, South Korea
9Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea
10Department of Psychiatry, Gil Medical Center, Gachon University, Incheon, South Korea
11Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital, Seongnam, South Korea
12Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
13Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
14Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Correspondence to: Hong-Hee Won
Correspondence may also be addressed to: Woojae Myung
†,‡These authors contributed equally to this work.
Abstract
Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies (GWAS) have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale GWAS of occupational attainment with 248,847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10−8); 12 were novel variants, unassociated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986, and rs1627527. The single nucleotide polymorphism (SNP)-based heritability was estimated to be 8.5% (s.e. = 0.004) and partitioned heritability was enriched in the central nervous system and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction, and neuropsychiatric disorders. In two-sample Mendelian randomization (MR) analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease (OR = 0.78, 95% CI = 0.65–0.92 in inverse variance weighted (IVW) method; OR = 0.73, 95% CI = 0.57–0.92 in the weighted median (WM) method). This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic SNPs (OR = 0.72, 95% CI = 0.57–0.91 in the IVW method; OR = 0.72, 95% CI = 0.53–0.97 in the WM method). Multivariable MR confirmed that occupational attainment had an independent effect on the risk for Alzheimer’s disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54–0.95 in the IVW method; OR = 0.68, 95% CI = 0.48–0.97 in the WM method).
Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.
Keywords : occupational attainment, cognitive reserve, genome-wide association study, Alzheimer’s disease, Mendelian randomization
논문정보
- Research article
- 2021년 10월 (BRIC 등록일 2021-10-12)
- 국내(교신)+국외 연구진
- 의약학 > 유전 및 유전체의학
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