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Genetic associations of protein-coding variants in human disease

Sun, Benjamin B. ; Kurki, Mitja I. ; Foley, Christopher N. ; [et al.]

Springer Science and Business Media LLC ; 2022

In: Nature Vol. 603, No. 7899 ( 2022-03-03), p. 95-102

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In: Nature, Springer Science and Business Media LLC, Vol. 603, No. 7899 ( 2022-03-03), p. 95-102

Abstract: Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes 1 . Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.

Type of Medium: Online Resource

ISSN: 0028-0836 , 1476-4687

URL: Article

DOI: 10.1038/s41586-022-04394-w

RVK:

TA 1000

RVK:

UA 1000

RVK:

WA 15000

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 120714-3

detail.hit.zdb_id: 1413423-8

SSG: 11

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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol

Lange, Leslie A. ; Hu, Youna ; Zhang, He ; [et al.]

Elsevier BV ; 2014

In: The American Journal of Human Genetics Vol. 94, No. 2 ( 2014-02), p. 233-245

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In: The American Journal of Human Genetics, Elsevier BV, Vol. 94, No. 2 ( 2014-02), p. 233-245

Type of Medium: Online Resource

ISSN: 0002-9297

URL: Article

DOI: 10.1016/j.ajhg.2014.01.010

RVK:

XA 10000

Language: English

Publisher: Elsevier BV

Publication Date: 2014

detail.hit.zdb_id: 1473813-2

SSG: 12

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Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Hancock, Dana B. ; Artigas, María Soler ; Gharib, Sina A. ; [et al.]

Public Library of Science (PLoS) ; 2012

In: PLoS Genetics Vol. 8, No. 12 ( 2012-12-20), p. e1003098-

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In: PLoS Genetics, Public Library of Science (PLoS), Vol. 8, No. 12 ( 2012-12-20), p. e1003098-

Type of Medium: Online Resource

ISSN: 1553-7404

URL: Article

DOI: 10.1371/journal.pgen.1003098

DOI: 10.1371/journal.pgen.1003098.g001

DOI: 10.1371/journal.pgen.1003098.g002

DOI: 10.1371/journal.pgen.1003098.t001

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DOI: 10.1371/journal.pgen.1003098.s010

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DOI: 10.1371/journal.pgen.1003098.s015

DOI: 10.1371/journal.pgen.1003098.s016

DOI: 10.1371/journal.pgen.1003098.s017

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2012

detail.hit.zdb_id: 2186725-2

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Genome-wide association analysis identifies six new loci associated with forced vital capacity

Loth, Daan W ; Artigas, María Soler ; Gharib, Sina A ; [et al.]

Springer Science and Business Media LLC ; 2014

In: Nature Genetics Vol. 46, No. 7 ( 2014-07), p. 669-677

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In: Nature Genetics, Springer Science and Business Media LLC, Vol. 46, No. 7 ( 2014-07), p. 669-677

Type of Medium: Online Resource

ISSN: 1061-4036 , 1546-1718

URL: Article

DOI: 10.1038/ng.3011

RVK:

XA 10000

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2014

detail.hit.zdb_id: 1494946-5

SSG: 12

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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Tang, Wenbo ; Kowgier, Matthew ; Loth, Daan W. ; [et al.]

Public Library of Science (PLoS) ; 2014

In: PLoS ONE Vol. 9, No. 7 ( 2014-7-1), p. e100776-

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In: PLoS ONE, Public Library of Science (PLoS), Vol. 9, No. 7 ( 2014-7-1), p. e100776-

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

DOI: 10.1371/journal.pone.0100776

DOI: 10.1371/journal.pone.0100776.g001

DOI: 10.1371/journal.pone.0100776.g002

DOI: 10.1371/journal.pone.0100776.t001

DOI: 10.1371/journal.pone.0100776.t002

DOI: 10.1371/journal.pone.0100776.t003

DOI: 10.1371/journal.pone.0100776.t004

DOI: 10.1371/journal.pone.0100776.s001

DOI: 10.1371/journal.pone.0100776.s002

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2014

detail.hit.zdb_id: 2267670-3

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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

Artigas, María Soler ; The International Lung Cancer Consortium ; Loth, Daan W ; [et al.]

Springer Science and Business Media LLC ; 2011

In: Nature Genetics Vol. 43, No. 11 ( 2011-11), p. 1082-1090

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In: Nature Genetics, Springer Science and Business Media LLC, Vol. 43, No. 11 ( 2011-11), p. 1082-1090

Type of Medium: Online Resource

ISSN: 1061-4036 , 1546-1718

URL: Article

DOI: 10.1038/ng.941

RVK:

XA 10000

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2011

detail.hit.zdb_id: 1494946-5

SSG: 12

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Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

Wilk, Jemma B. ; Shrine, Nick R. G. ; Loehr, Laura R. ; [et al.]

American Thoracic Society ; 2012

In: American Journal of Respiratory and Critical Care Medicine Vol. 186, No. 7 ( 2012-10-01), p. 622-632

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In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 186, No. 7 ( 2012-10-01), p. 622-632

Type of Medium: Online Resource

ISSN: 1073-449X , 1535-4970

URL: Article

DOI: 10.1164/rccm.201202-0366OC

RVK:

XA 21200

Language: English

Publisher: American Thoracic Society

Publication Date: 2012

detail.hit.zdb_id: 1468352-0

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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Shah, Sonia ; Henry, Albert ; Roselli, Carolina ; [et al.]

Springer Science and Business Media LLC ; 2020

In: Nature Communications Vol. 11, No. 1 ( 2020-01-09)

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In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-01-09)

Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development ( MYOZ1 , SYNPO2L ), protein homoeostasis ( BAG3 ), and cellular senescence ( CDKN1A ). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-019-13690-5

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2553671-0

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Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Smith, J. Gustav ; Felix, Janine F. ; Morrison, Alanna C. ; [et al.]

Public Library of Science (PLoS) ; 2016

In: PLOS Genetics Vol. 12, No. 5 ( 2016-5-5), p. e1006034-

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In: PLOS Genetics, Public Library of Science (PLoS), Vol. 12, No. 5 ( 2016-5-5), p. e1006034-

Type of Medium: Online Resource

ISSN: 1553-7404

URL: Article

DOI: 10.1371/journal.pgen.1006034

DOI: 10.1371/journal.pgen.1006034.g001

DOI: 10.1371/journal.pgen.1006034.g002

DOI: 10.1371/journal.pgen.1006034.t001

DOI: 10.1371/journal.pgen.1006034.t002

DOI: 10.1371/journal.pgen.1006034.s001

DOI: 10.1371/journal.pgen.1006034.s002

DOI: 10.1371/journal.pgen.1006034.s003

DOI: 10.1371/journal.pgen.1006034.s004

DOI: 10.1371/journal.pgen.1006034.s005

DOI: 10.1371/journal.pgen.1006034.s006

DOI: 10.1371/journal.pgen.1006034.s007

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DOI: 10.1371/journal.pgen.1006034.s009

DOI: 10.1371/journal.pgen.1006034.s010

DOI: 10.1371/journal.pgen.1006034.s011

DOI: 10.1371/journal.pgen.1006034.s012

DOI: 10.1371/journal.pgen.1006034.s013

DOI: 10.1371/journal.pgen.1006034.s014

DOI: 10.1371/journal.pgen.1006034.s015

DOI: 10.1371/journal.pgen.1006034.s016

DOI: 10.1371/journal.pgen.1006034.s017

DOI: 10.1371/journal.pgen.1006034.s018

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2016

detail.hit.zdb_id: 2186725-2

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The genomics of heart failure: design and rationale of the HERMES consortium

Lumbers, R. Thomas ; Shah, Sonia ; Lin, Honghuang ; [et al.]

Wiley ; 2021

In: ESC Heart Failure Vol. 8, No. 6 ( 2021-12), p. 5531-5541

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In: ESC Heart Failure, Wiley, Vol. 8, No. 6 ( 2021-12), p. 5531-5541

Abstract: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P 〈 5 × 10 −8 under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Type of Medium: Online Resource

ISSN: 2055-5822 , 2055-5822

URL: Issue

URL: Article

DOI: 10.1002/ehf2.v8.6

DOI: 10.1002/ehf2.13517

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 2814355-3

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