Genetic Pleiotropy between Nicotine Dependence and Respiratory Outcomes

Zhang, Jushan; Peng, Shouneng; Cheng, Haoxiang; Nomura, Yoko; Narzo, Antonio Fabio Di; Hao, Ke

doi:10.1038/s41598-017-16964-4

Cited by 10 publications

(7 citation statements)

References 32 publications

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“…It is known that most genomic loci can affect several traits either by affecting multiple genes at the locus or genetic pleiotropy (29)(30)(31). In our results, risk loci of the GWAS catalog affected by CNVs we detected in either the FA or the STARNET data were linked to multiple traits.…”

Section: Functional Relevance Of Cnvsupporting

confidence: 59%

EnsembleCNV: An ensemble machine learning algorithm to identify and genotype copy number variation using SNP array data

Zhang

Cheng

Hong

et al. 2018

Preprint

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The associations between diseases/traits and copy number variants (CNVs) have not been systematically investigated in genome-wide association studies (GWASs), primarily due to a lack of robust and accurate tools for CNV genotyping. Herein, we propose a novel ensemble learning framework, ensembleCNV, to detect and genotype CNVs using single nucleotide polymorphism (SNP) array data. EnsembleCNV a) identifies and eliminates batch effects at raw data level; b) assembles individual CNV calls into CNV regions (CNVRs) from multiple existing callers with complementary strengths by a heuristic algorithm; c) re-genotypes each CNVR with local likelihood model adjusted by global information across multiple CNVRs; d) refines CNVR boundaries by local correlation structure in copy number intensities; e) provides direct CNV genotyping accompanied with confidence score, directly accessible for downstream quality control and association analysis. Benchmarked on two large datasets, ensembleCNV outperformed competing methods and achieved a high call rate (93.3%) and reproducibility (98.6%), while concurrently achieving high sensitivity by capturing 85% of common CNVs documented in the 1000 Genomes Project. Given this CNV call rate and accuracy, which are comparable to SNP genotyping, we suggest ensembleCNV holds significant promise for performing genome-wide CNV association studies and investigating how CNVs predispose to human diseases.

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Section: Functional Relevance Of Cnvsupporting

confidence: 59%

EnsembleCNV: An ensemble machine learning algorithm to identify and genotype copy number variation using SNP array data

Zhang

Cheng

Hong

et al. 2018

Preprint

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“…The PRS, representing estimated genetic determinants for five traits (HDL, LDL, triglycerides, T2D, and type 1 MI) were computed following the thresholding-pruning procedure [ 53 ]. We computed PRS for EA sub-cohort of PLWH (PLWH EA ) and AA sub-cohort of PLWH (PLWH AA ) separately using linear combinations of the imputed genotype dosages [ 54 ], and regression coefficients from the respective summary association statistics retrieved from previously published GWAS conducted in the general population largely of European ancestry: Global Lipids Genetics Consortium (GLGC) [ 31 ]; Genetic Investigation of ANthropometric Traits (GIANT) consortium [ 32 ]; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium [ 28 ]; Coronary ARtery DIsease Genome wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) consortium [ 29 ]; and UKBiobank CardioMetabolic Consortium [ 30 ] (PRS GEN, Additional file 1 : Table S2). For each disease/trait, we calculated eight sets of PRS using GWAS p value thresholds of 1E−1, 1E−2, 1E−3, 1E−4, 1E−5, 1E−6, 1E−7, and 1E−8 for including SNPs in the PRS derivation.…”

Section: Methodsmentioning

confidence: 99%

Genetic architecture of cardiometabolic risks in people living with HIV

Cheng

Sewda

Márquez-Luna

et al. 2020

BMC Med

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Background Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown. Methods We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH. Results We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI. Conclusions Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

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“…There are two possible explanations for this finding: (a) the smoking measurement used (average cigarettes smoked per day) does not accurately capture the pathological effects of smoking and the observed association of rs17486278 to FEV 1 /FVC is a result of residual confounding; or (b) independent of smoking, genotype at rs17486278 affects airflow limitation. Previous studies have presented contradictory evidence of these explanations (Obeidat et al, 2018;Siedlinski et al, 2013;Vanderweele et al, 2012;Wilk et al, 2012;Zhang et al, 2017). While there is evidence of association between CHRNA5 and lung function in neversmokers (Wilk et al, 2012), suggesting an independent effect on lung function, recent analyses have found no association of this region with lung function or lung cancer in never-smokers (Obeidat et al, 2018;Wang, Broderick, Matakidou, Eisen, & Houlston, 2011).…”

Section: Discussionmentioning

confidence: 98%

“…Previous studies have presented contradictory evidence of these explanations (Obeidat et al, 2018;Siedlinski et al, 2013;Vanderweele et al, 2012;Wilk et al, 2012;Zhang et al, 2017). Although the association of the 15q25.1 locus (which includes genes coding for nicotinic acetylcholine receptors) with nicotine dependence is indisputable, evidence for its independent association with airflow obstruction is variable.…”

Section: Discussionmentioning

confidence: 99%

Assessing pleiotropy and mediation in genetic loci associated with chronic obstructive pulmonary disease

Parker

Lutz

Hobbs

et al. 2019

Genetic Epidemiology

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Genetic association studies have increasingly recognized variant effects on multiple phenotypes. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with environmental and genetic causes. Multiple genetic variants have been associated with COPD, many of which show significant associations to additional phenotypes. However, it is unknown if these associations represent biological pleiotropy or if they exist through correlation of related phenotypes (“mediated pleiotropy”). Using 6,670 subjects from the COPDGene study, we describe the association of known COPD susceptibility loci with other COPD‐related phenotypes and distinguish if these act directly on the phenotypes (i.e., biological pleiotropy) or if the association is due to correlation (i.e., mediated pleiotropy). We identified additional associated phenotypes for 13 of 25 known COPD loci. Tests for pleiotropy between genotype and associated outcomes were significant for all loci. In cases of significant pleiotropy, we performed mediation analysis to test if SNPs had a direct association to phenotype. Most loci showed a mediated effect through the hypothesized causal pathway. However, many loci also had direct associations, suggesting causal explanations (i.e., emphysema leading to reduced lung function) are incomplete. Our results highlight the high degree of pleiotropy in complex disease‐associated loci and provide novel insights into the mechanisms underlying COPD.

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Genetic Pleiotropy between Nicotine Dependence and Respiratory Outcomes

Cited by 10 publications

References 32 publications

EnsembleCNV: An ensemble machine learning algorithm to identify and genotype copy number variation using SNP array data

EnsembleCNV: An ensemble machine learning algorithm to identify and genotype copy number variation using SNP array data

Genetic architecture of cardiometabolic risks in people living with HIV

Assessing pleiotropy and mediation in genetic loci associated with chronic obstructive pulmonary disease

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