PMID- 34050728
OWN - NLM
STAT- MEDLINE
DCOM- 20230413
LR  - 20230416
IS  - 1367-4811 (Electronic)
IS  - 1367-4803 (Linking)
VI  - 37
IP  - 22
DP  - 2021 Nov 18
TI  - A framework to decipher the genetic architecture of combinations of complex 
      diseases: applications in cardiovascular medicine.
PG  - 4137-4147
LID - 10.1093/bioinformatics/btab417 [doi]
AB  - MOTIVATION: Currently, most genome-wide association studies (GWAS) are studies of 
      a single disease against controls. However, an individual is often affected by 
      more than one condition. For example, coronary artery disease (CAD) is often 
      comorbid with type 2 diabetes mellitus (T2DM). Similarly, it is clinically 
      meaningful to study patients with one disease but without a related comorbidity. 
      For example, obese T2DM may have different pathophysiology from nonobese T2DM. 
      RESULTS: We developed a statistical framework (CombGWAS) to uncover 
      susceptibility variants for comorbid disorders (or a disorder without 
      comorbidity), using GWAS summary statistics only. In essence, we mimicked a 
      case-control GWAS in which the cases are affected with comorbidities or a disease 
      without comorbidity. We extended our methodology to analyze continuous traits 
      with clinically meaningful categories (e.g. lipids), and combination of more than 
      two traits. We verified the feasibility and validity of our method by applying it 
      to simulated scenarios and four cardiometabolic (CM) traits. In total, we 
      identified 384 and 587 genomic risk loci respectively for 6 comorbidities and 12 
      CM disease 'subtypes' without a relevant comorbidity. Genetic correlation 
      analysis revealed that some subtypes may be biologically distinct from others. 
      Further Mendelian randomization analysis showed differential causal effects of 
      different subtypes to relevant complications. For example, we found that obese 
      T2DM is causally related to increased risk of CAD (P = 2.62E-11). AVAILABILITY 
      AND IMPLEMENTATION: R code is available at: 
      https://github.com/LiangyingYin/CombGWAS. SUPPLEMENTARY INFORMATION: 
      Supplementary data are available at Bioinformatics online.
CI  - (c) The Author(s) 2021. Published by Oxford University Press. All rights reserved. 
      For permissions, please e-mail: journals.permissions@oup.com.
FAU - Yin, Liangying
AU  - Yin L
AUID- ORCID: 0000-0002-1029-7317
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, China.
FAU - Chau, Carlos Kwan-Long
AU  - Chau CK
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, China.
FAU - Lin, Yu-Ping
AU  - Lin YP
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, China.
FAU - Rao, Shitao
AU  - Rao S
AUID- ORCID: 0000-0002-3604-4684
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, China.
AD  - Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, 
      School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, 
      China.
AD  - Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of 
      Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
FAU - Xiang, Yong
AU  - Xiang Y
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, China.
FAU - Sham, Pak-Chung
AU  - Sham PC
AD  - Department of Psychiatry, University of Hong Kong, Hong Kong SAR, China.
FAU - So, Hon-Cheong
AU  - So HC
AUID- ORCID: 0000-0002-7102-833X
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, China.
AD  - KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common 
      Diseases, Kunming Institute of Zoology and The Chinese University of Hong Kong, 
      Hong Kong SAR, China.
AD  - Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, 
      China.
AD  - CUHK Shenzhen Research Institute, Shenzhen, China.
AD  - Margaret K.L. Cheung Research Centre for Management of Parkinsonism, The Chinese 
      University of Hong Kong, Hong Kong SAR, China.
AD  - Brain and Mind Institute, The Chinese University of Hong Kong, Hong Kong SAR, 
      China.
AD  - Hong Kong Branch of the Chinese Academy of Sciences Center for Excellence in 
      Animal Evolution and Genetics, The Chinese University of Hong Kong, Hong Kong 
      SAR, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Bioinformatics
JT  - Bioinformatics (Oxford, England)
JID - 9808944
SB  - IM
MH  - Humans
MH  - *Diabetes Mellitus, Type 2/genetics
MH  - Genome-Wide Association Study/methods
MH  - Polymorphism, Single Nucleotide
MH  - *Coronary Artery Disease/genetics
MH  - Obesity
EDAT- 2021/05/30 06:00
MHDA- 2023/04/13 06:42
CRDT- 2021/05/29 12:06
PHST- 2021/01/04 00:00 [received]
PHST- 2021/05/22 00:00 [revised]
PHST- 2021/05/28 00:00 [accepted]
PHST- 2023/04/13 06:42 [medline]
PHST- 2021/05/30 06:00 [pubmed]
PHST- 2021/05/29 12:06 [entrez]
AID - 6288448 [pii]
AID - 10.1093/bioinformatics/btab417 [doi]
PST - ppublish
SO  - Bioinformatics. 2021 Nov 18;37(22):4137-4147. doi: 
      10.1093/bioinformatics/btab417.