Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits

Abstract Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.

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Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

10.1101/2020.01.15.898858 ◽

2020 ◽

Author(s):

Bryan C. Quach ◽

Michael J. Bray ◽

Nathan C. Gaddis ◽

Mengzhen Liu ◽

Teemu Palviainen ◽

...

Keyword(s):

Nicotine Dependence ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

African Ancestry ◽

Multiple Traits ◽

Expression Of Genes ◽

Genome Wide ◽

A Genome ◽

The Uk ◽

Smoking Index

AbstractCigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (rg=0.40–0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

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HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases

Genome Biology ◽

10.1186/s13059-019-1844-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 9

Author(s):

Daniel M. Jordan ◽

Marie Verbanck ◽

Ron Do

Keyword(s):

Genetic Variation ◽

Genetic Architecture ◽

Genome Wide Association ◽

Summary Statistics ◽

Human Genetic Variation ◽

Uk Biobank ◽

Multiple Traits ◽

Genome Wide ◽

Quantitative Score ◽

Independent Effects

Abstract Horizontal pleiotropy, where one variant has independent effects on multiple traits, is important for our understanding of the genetic architecture of human phenotypes. We develop a method to quantify horizontal pleiotropy using genome-wide association summary statistics and apply it to 372 heritable phenotypes measured in 361,194 UK Biobank individuals. Horizontal pleiotropy is pervasive throughout the human genome, prominent among highly polygenic phenotypes, and enriched in active regulatory regions. Our results highlight the central role horizontal pleiotropy plays in the genetic architecture of human phenotypes. The HOrizontal Pleiotropy Score (HOPS) method is available on Github at https://github.com/rondolab/HOPS.

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O21: GENOME-WIDE ASSOCIATION STUDY OF VARICOSE VEINS IN 810,625 INDIVIDUALS IDENTIFIES 45 GENETIC RISK LOCI

British Journal of Surgery ◽

10.1093/bjs/znab117.021 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

WUR Ahmed ◽

A Wiberg ◽

M Ng ◽

D Furniss

Keyword(s):

Association Study ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Varicose Veins ◽

Phenotypic Expression ◽

Cell Activity ◽

Genome Wide Association ◽

Uk Biobank ◽

Genetic Components ◽

Genome Wide

Abstract Introduction Varicose veins (VV) impact a third of the UK adult population; 10% of patients develop lipodermatosclerosis and ulceration. VV often requires surgical management, however, there is a high-risk of recurrence. VV is a complex disease, where genetic and non-genetic components contribute to overall phenotypic expression. The genetic architecture of VV is poorly understood; we aimed to uncover its genetic basis. Method We conducted hitherto the largest genome-wide association study of VV. In stage one, using UK Biobank, we compared 22,473 VV patients and 379,183 controls. In stage two, replication and meta-analysis were performed in an independent cohort of 113,041 VV cases and 295,928 controls from 23&Me (California, USA). In-silico analysis was conducted in FUMA, MAGMA, and XGR. Result 109 genome-wide significant (P≤ 5×10-8) loci were identified in UK Biobank, 45 of which successfully replicated in the 23&Me cohort. Twenty-seven loci have not been previously reported. FUMA positionally-mapped 128 genes at the replicated loci, with 84 having a combined annotation-dependent depletion score (CADD) >12.37, suggesting functional, deleterious variants. MAGMA analysis implicated pathways involved in cardiovascular system development (P=1.57×10-08) and tube morphogenesis (P=9.35×10-08). Furthermore, XGR revealed enriched pathways in downstream signalling in naive CD8+ T cells (P=0.0017), and encoding structural and core extracellular glycoproteins (both P=0.007). Conclusion We identified 45 variants conferring risk of VV, which provide insights into disease biology. Implicated genes are enriched in pathways involved in vascular development, immune cell activity and extracellular matrix function, and provide new targets for therapeutic development. Take-home message Unravelling the genetic architecture of varicose veins may facilitate our understanding of the disease and guide therapeutic approaches.

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Genome-Wide Association Study and Genetic Correlation Scan Provide Insights into Its Genetic Architecture of Sleep Health Score in the UK Biobank Cohort

Nature and Science of Sleep ◽

10.2147/nss.s326818 ◽

2022 ◽

Vol Volume 14 ◽

pp. 1-12

Author(s):

Yao Yao ◽

Yumeng Jia ◽

Yan Wen ◽

Bolun Cheng ◽

Shiqiang Cheng ◽

...

Keyword(s):

Association Study ◽

Genetic Correlation ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Uk Biobank ◽

Sleep Health ◽

Health Score ◽

Genome Wide ◽

The Uk

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HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases

10.1101/311332 ◽

2018 ◽

Cited By ~ 6

Author(s):

Daniel M. Jordan ◽

Marie Verbanck ◽

Ron Do

Keyword(s):

Genetic Variation ◽

Genetic Architecture ◽

Genome Wide Association ◽

Summary Statistics ◽

Human Genetic Variation ◽

Uk Biobank ◽

Multiple Traits ◽

Genome Wide ◽

Quantitative Score ◽

Independent Effects

AbstractHorizontal pleiotropy, where one variant has independent effects on multiple traits, is important for our understanding of the genetic architecture of human phenotypes. We develop a method to quantify horizontal pleiotropy using genome-wide association summary statistics and apply it to 372 heritable phenotypes measured in 361,194 UK Biobank individuals. Horizontal pleiotropy is pervasive throughout the human genome, prominent among highly polygenic phenotypes, and enriched in active regulatory regions. Our results highlight the central role horizontal pleiotropy plays in the genetic architecture of human phenotypes. The HOrizontal Pleiotropy Score (HOPS) method is available on Github at https://github.com/rondolab/HOPS.

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Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

Scientific Reports ◽

10.1038/s41598-021-85871-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Helena R. R. Wells ◽

Fatin N. Zainul Abidin ◽

Maxim B. Freidin ◽

Frances M. K. Williams ◽

Sally J. Dawson

Keyword(s):

Association Study ◽

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Uk Biobank ◽

Significance Threshold ◽

Genome Wide ◽

Final Sample ◽

Close Proximity ◽

Repressor Complex

AbstractTinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E−06.

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Eyes of Africa: The Genetics of Blindness: Study Design and Methodology

BMC Ophthalmology ◽

10.1186/s12886-021-02029-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Olusola Olawoye ◽

Chimdi Chuka-Okosa ◽

Onoja Akpa ◽

Tony Realini ◽

Michael Hauser ◽

...

Keyword(s):

Genome Wide Association Study ◽

Case Control Study ◽

African Ancestry ◽

Collaborative Study ◽

Data Set ◽

Human Heredity ◽

Genome Wide ◽

A Genome ◽

Multiplex Families ◽

Control Study

Abstract Background This report describes the design and methodology of the “Eyes of Africa: The Genetics of Blindness,” a collaborative study funded through the Human Heredity and Health in Africa (H3Africa) program of the National Institute of Health. Methods This is a case control study that is collecting a large well phenotyped data set among glaucoma patients and controls for a genome wide association study. (GWAS). Multiplex families segregating Mendelian forms of early-onset glaucoma will also be collected for exome sequencing. Discussion A total of 4500 cases/controls have been recruited into the study at the end of the 3rd funded year of the study. All these participants have been appropriately phenotyped and blood samples have been received from these participants. Recent GWAS of POAG in African individuals demonstrated genome-wide significant association with the APBB2 locus which is an association that is unique to individuals of African ancestry. This study will add to the existing knowledge and understanding of POAG in the African population.

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