Including diverse and admixed populations in genetic epidemiology research

Caliebe, Amke; Tekola‐Ayele, Fasil; Darst, Burcu F.; Wang, Xuexia; Song, Yeunjoo E.; Gui, Jiang; Sebro, Ronnie; Balding, David J.; Saad, Mohamad; Dubé, Marie‐Pierre

doi:10.1002/gepi.22492

Cited by 13 publications

(8 citation statements)

References 225 publications

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“…To identify common genetic variation associated with CMR-derived LVM, we performed a GWAS of indexed LVM using BOLT-LMM v2.3.4 50 , Article https://doi.org/10.1038/s41467-023-37173-w which accounts for ancestral heterogeneity, cryptic population structure, and sample relatedness by fitting a linear mixed model with a Bayesian mixture prior as a random effect 19,51,52 . Previous evidence supports the use of LMM approaches to perform GWAS of admixed populations, which may provide favorable statistical power 51,53,54 , and similar approaches have been taken previously 19,51,52 . The GWAS was performed among 43,230 individuals having undergone CMR imaging, after exclusion of individuals without genetic data meeting standard quality control metrics (e.g., no evidence of sex chromosome aneuploidy, outliers in heterozygosity and missing rates).…”

Section: Genome-wide Association Studymentioning

confidence: 59%

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass

et al. 2023

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Left ventricular mass is a risk marker for cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance is the gold-standard for left ventricular mass estimation, but is challenging to obtain at scale. Here, we use deep learning to enable genome-wide association study of cardiac magnetic resonance-derived left ventricular mass indexed to body surface area within 43,230 UK Biobank participants. We identify 12 genome-wide associations (1 known at TTN and 11 novel for left ventricular mass), implicating genes previously associated with cardiac contractility and cardiomyopathy. Cardiac magnetic resonance-derived indexed left ventricular mass is associated with incident dilated and hypertrophic cardiomyopathies, and implantable cardioverter-defibrillator implant. An indexed left ventricular mass polygenic risk score ≥90th percentile is also associated with incident implantable cardioverter-defibrillator implant in separate UK Biobank (hazard ratio 1.22, 95% CI 1.05-1.44) and Mass General Brigham (hazard ratio 1.75, 95% CI 1.12-2.74) samples. Here, we perform a genome-wide association study of cardiac magnetic resonance-derived indexed left ventricular mass to identify 11 novel variants and demonstrate that cardiac magnetic resonance-derived and genetically predicted indexed left ventricular mass are associated with incident cardiomyopathy.

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Section: Genome-wide Association Studymentioning

confidence: 59%

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass

et al. 2023

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“…It is well known that population- or ethnic-specific background is a key factor in polygenic scores and it is important for future studies to be inclusive of patients from diverse backgrounds. 36-38 To illustrate the importance of the study population in genetic scores, we performed a principal component analysis (PCA) using common SNPs that were consistently genotyped in all datasets. Additionally, we included the publicly available 1000 Genomes Project dataset as a validation for the clustering of the populations.…”

Section: Discussionmentioning

confidence: 99%

Interaction of mitochondrial polygenic score and environmental factors in LRRK2 p.Gly2019Ser parkinsonism

Lueth

Gabbert

Koenig

et al. 2023

Preprint

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The objective of our study was to investigate the impact of the mitochondrial polygenic score (MGS) and lifestyle/environmental data on age at onset in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic Parkinson's disease (iPD). In this study, we included N=486 patients with LRRK2-PD and N=9259 patients with iPD from AMP-PD, Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data was utilized to perform the MGS analysis, using 14 Single Nucleotide Polymorphisms (SNPs) from genes causally associated with mitochondrial function and PD risk. Additionally, lifestyle and environmental data were obtained from the PD risk factor questionnaire (PD-RFQ). Correlation analyses and linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO. We observed that higher MGS was associated with earlier AAO in patients with LRRK2-PD (p=4.0x10-4, beta=-0.18) but not in patients with iPD. A correlation between MGS and AAO was visibly stronger in European ancestry LRRK2-PD patients (p=0.01, r=-0.16) than in Tunisian Arab-Berber patients (p=0.44, r=-0.05). We found that the MGS interacted with coffee (p=0.03, beta=-0.38) and caffeinated soda consumption (p=0.03, beta=-0.37) in LRRK2-PD and with caffeine soda consumption (p=0.047, beta=-0.22) and pesticide exposure (p=0.02, beta=-0.37) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeine or were exposed to pesticides. The MGS related to mitochondrial function was associated with AAO in LRRK2-PD but not iPD with an ethnic-specific effect. Caffeine consumption or pesticide exposure interacted with MGS to predict PD AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2-PD.

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“…Though we see an overall association between the MGS and AAO, when separating the cohorts, the association was found to be more pronounced in the European cohorts and visibly weaker in the Tunisian/Arab cohort in the correlation analysis. It is well known that population‐ or ethnic‐specific background is a key factor in polygenic scores and it is important for future studies to be inclusive of patients from diverse backgrounds 39‐41 . To illustrate the importance of the study population in genetic scores, we performed a PCA using common SNPs.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that populationor ethnic-specific background is a key factor in polygenic scores and it is important for future studies to be inclusive of patients from diverse backgrounds. [39][40][41] To illustrate the importance of the study population in genetic scores, we performed a PCA using common SNPs. Additionally, we included the publicly available 1000 Genomes Project dataset as a validation for the clustering of the populations.…”

Section: G S I S a S S O C I A T E D W I T Hmentioning

confidence: 99%

Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism

et al. 2023

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BackgroundA mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk.ObjectiveTo investigate the impact of the MGS and lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2‐PD) and idiopathic PD (iPD).MethodsWe included N = 486 patients with LRRK2‐PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP‐PD), Fox Insight, and a Tunisian Arab‐Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD‐RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO.ResultsOur derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10−8). We observed that higher MGS was significantly associated with earlier AAO in LRRK2‐PD (P = 0.047, β = −1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, β = 0.22). There was a correlation between MGS and AAO in LRRK2‐PD patients of European descent (P = 0.049, r = −0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = −0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, β = −5.65) in LRRK2‐PD and with tobacco use (P = 0.010, β = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non‐smokers.ConclusionsThe MGS was more strongly associated with earlier AAO in LRRK2‐PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene–environment interactions as modifiers of AAO in LRRK2‐PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Including diverse and admixed populations in genetic epidemiology research

Cited by 13 publications

References 225 publications

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass

Interaction of mitochondrial polygenic score and environmental factors in LRRK2 p.Gly2019Ser parkinsonism

Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism

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