Using Phenotypic Heterogeneity to Increase the Power of Genome-Wide Association Studies: Application to Age at Onset of Ischaemic Stroke Subphenotypes

2013 ◽  
Vol 37 (5) ◽  
pp. 495-503 ◽  
Author(s):  
Matthew Traylor ◽  
Steve Bevan ◽  
Peter M. Rothwell ◽  
Cathie Sudlow ◽  
Martin Dichgans ◽  
...  
Keyword(s):  
Ischaemic Stroke ◽  
Association Studies ◽  
Age At Onset ◽  
Phenotypic Heterogeneity ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Genome-wide association studies of cognitive and motor progression in Parkinson's disease

2020 ◽  
Author(s):  
Manuela MX Tan ◽  
Michael A Lawton ◽  
Edwin Jabbari ◽  
Regina H Reynolds ◽  
Hirotaka Iwaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Association Studies ◽  
Age At Onset ◽  
Case Control ◽  
New Method ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies (GWASs) have identified variants associated with disease risk, but not progression. Objective: To identify genetic variants associated with PD progression in GWASs. Methods: We analysed three large, longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3,364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, where we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analysed in linear regressions in GWASs. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. Results: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ϵ4 tagging variant, rs429358, was significantly associated with the rate of composite and cognitive progression in PD. No single variants were associated with motor progression. However in gene-based analysis, variation across ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (p=5.3 x 10^-6). Conclusions: This new method in PD improves measurement of symptom progression. We provide strong evidence that the APOE ϵ4 allele drives progressive cognitive impairment in PD. We have also reported loci of interest which need to be tested in further studies.

scholarly journals Genetics of Common Polygenic Ischaemic Stroke: Current Understanding and Future Challenges

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Steve Bevan ◽  
Hugh S. Markus
Keyword(s):  
Risk Factors ◽  
Ischaemic Stroke ◽  
Stroke Risk ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genetic Risks ◽  
Future Challenges ◽  
Candidate Gene Studies

Stroke is the third commonest cause of death and the major cause of adult neurological disability worldwide. While much is known about conventional risk factors such as hypertension, diabetes and incidence of smoking, these environmental factors only account for a proportion of stroke risk. Up to 50% of stroke risk can be attributed to genetic risk factors, although to date no single risk allele has been convincingly identified as contributing to this risk. Advances in the field of genetics, most notably genome wide association studies (GWAS), have revealed genetic risks in other cardiovascular disease and these techniques are now being applied to ischaemic stroke. This paper covers previous genetic studies in stroke including candidate gene studies, discusses the genome wide association approach, and future techniques such as next generation sequencing and the post-GWAS era. The review also considers the overlap from other cardiovascular diseases and whether findings from these may also be informative in ischaemic stroke.

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