Rare variant contribution to the heritability of coronary artery disease

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1038/s41467-024-52939-6

Rare variant contribution to the heritability of coronary artery disease

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Original language	English (US)
Article number	8741
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-52939-6
State	Published - Dec 2024

Funding

This study was supported by National Heart, Lung and Blood Institute (NHLBI) grant R01 HL146860. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. WGS for \u201CNHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish\u201D (phs000956.v4.p1) was performed at the Broad Institute Genomics Platform (3R01HL121007-01S1). WGS for \u201CNHLBI TOPMed: Atherosclerosis Risk in Communities (ARIC)\u201D (phs001211.v3.p2) was performed at the Broad Institute Genomics Platform (3R01HL092577-06S1) and at the Baylor College of Medicine Human Genome Sequencing Center (3U54HG003273-12S2 / HHSN268201500015C). WGS for \u201CNHLBI TOPMed: Mount Sinai BioMe Biobank\u201D (phs001644.v1.p1) was performed at the McDonnell Genome Institute (3UM1HG008853-01S2). WGS for \u201CNHLBI TOPMed: Coronary Artery Risk Development in Young Adults (CARDIA)\u201D (phs001612.v1.p1) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201600033I). WGS for \u201CNHLBI TOPMed: Cardiovascular Health Study (CHS)\u201D (phs001368.v2.p2) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201600033I, 3U54HG003273-12S2 / HHSN268201500015C) and at the Broad Institute Genomics Platform (HHSN268201600034I). WGS for \u201CNHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene)\u201D (phs000951.v4.p4) was performed at the Broad Institute Genomics Platform (HHSN268201500014C, HHSN268201500014C) and at the Northwest Genomics Center (3R01HL089856-08S1). WGS for \u201CNHLBI TOPMed: Diabetes Heart Study (DHS)\u201D (phs001412.v2.p1) was performed at the Broad Institute Genomics Platform (HHSN268201500014C). WGS for \u201CNHLBI TOPMed: Framingham Heart Study (FHS)\u201D (phs000974.v4.p3) was performed at the Broad Institute Genomics Platform (3U54HG003067-12S2, HHSN268201600034I, 3R01HL092577-06S1). WGS for \u201CNHLBI TOPMed: Genetic Studies of Atherosclerosis Risk (GeneSTAR)\u201D (phs001218.v2.p1) was performed at the Broad Institute Genomics Platform (HHSN268201500014C), at Illumina (R01HL112064) and at Psomagen (3R01HL112064-04S1). WGS for \u201CNHLBI TOPMed: Genetic Epidemiology Network of Arteriopathy (GENOA)\u201D (phs001345.v2.p1) was performed at the Broad Institute Genomics Platform (HHSN268201500014C) and at the Northwest Genomics Center (3R01HL055673-18S1). WGS for \u201CNHLBI TOPMed: Jackson Heart Study (JHS)\u201D (phs000964.v4.p1) was performed at the Northwest Genomics Center (HHSN268201100037C). WGS for \u201CNHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)\u201D (phs001416.v2.p1) was performed at the Broad Institute Genomics Platform (HHSN268201600034I, 3U54HG003067-13S1, HHSN268201500014C). WGS for \u201CNHLBI TOPMed: Women\u2019s Health Initiative (WHI)\u201D (phs001237.v2.p1) was performed at the Broad Institute Genomics Platform (HHSN268201500014C). Core support, including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity QC, and general program coordination, was provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Consortium members are listed in the Supplementary Information. P.T.E. is supported by grants from the National Institutes of Health (1RO1HL092577, 1R01HL157635, 5R01HL139731), from the American Heart Association Strategically Focused Research Networks (18SFRN34230127), and from the European Union (MAESTRIA 965286). C.L.M. is supported by NIH/NHLBI grants (R01HL148239 and R01HL164577), Fondation Leducq \u2018PlaqOmics\u2019 (18CVD02), and the Chan Zuckerberg Initiative, LLC and Silicon Valley Community Foundation. R.D. is supported by the National Institute of General Medical Sciences of the NIH (R35-GM124836) and the National Heart, Lung and Blood Institute of the NIH (R01-HL139865 and R01-HL155915). This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. Research reported in this publication was also supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD026880 and S10OD030463. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services. P.T.E. receives sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG, MyoKardia and Novartis. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat). C.L.M. received grant support from AstraZeneca for unrelated work. R.D. reported being a scientific co-founder, consultant and equity holder for Pensieve Health and being a consultant for Variant Bio, all not related to this work. All other authors declare no competing interests.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-024-52939-6

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title = "Rare variant contribution to the heritability of coronary artery disease",

abstract = "Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.",

author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Ghislain Rocheleau and Clarke, {Shoa L.} and Ga{\"e}lle Auguste and Hasbani, {Natalie R.} and Morrison, {Alanna C.} and Heath, {Adam S.} and Bielak, {Lawrence F.} and Iyer, {Kruthika R.} and Young, {Erica P.} and Stitziel, {Nathan O.} and Goo Jun and Cecelia Laurie and Broome, {Jai G.} and Khan, {Alyna T.} and Arnett, {Donna K.} and Becker, {Lewis C.} and Bis, {Joshua C.} and Eric Boerwinkle and Bowden, {Donald W.} and Carson, {April P.} and Ellinor, {Patrick T.} and Myriam Fornage and Nora Franceschini and Freedman, {Barry I.} and Heard-Costa, {Nancy L.} and Lifang Hou and Chen, {Yii Der Ida} and Kenny, {Eimear E.} and Charles Kooperberg and Kral, {Brian G.} and Loos, {Ruth J.F.} and Lutz, {Sharon M.} and Manson, {Jo Ann E.} and Martin, {Lisa W.} and Mitchell, {Braxton D.} and Rami Nassir and Palmer, {Nicholette D.} and Post, {Wendy S.} and Preuss, {Michael H.} and Psaty, {Bruce M.} and Raffield, {Laura M.} and Regan, {Elizabeth A.} and Rich, {Stephen S.} and Smith, {Jennifer A.} and Taylor, {Kent D.} and Yanek, {Lisa R.} and Young, {Kendra A.} and Zhao, {Snow Xueyan} and Ivana Yang and Weng, {Lu Chen}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-52939-6",

language = "English (US)",

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AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

AU - Rocheleau, Ghislain

AU - Clarke, Shoa L.

AU - Auguste, Gaëlle

AU - Hasbani, Natalie R.

AU - Morrison, Alanna C.

AU - Heath, Adam S.

AU - Bielak, Lawrence F.

AU - Iyer, Kruthika R.

AU - Young, Erica P.

AU - Stitziel, Nathan O.

AU - Jun, Goo

AU - Laurie, Cecelia

AU - Broome, Jai G.

AU - Khan, Alyna T.

AU - Arnett, Donna K.

AU - Becker, Lewis C.

AU - Bis, Joshua C.

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

AU - Carson, April P.

AU - Ellinor, Patrick T.

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Freedman, Barry I.

AU - Heard-Costa, Nancy L.

AU - Hou, Lifang

AU - Chen, Yii Der Ida

AU - Kenny, Eimear E.

AU - Kooperberg, Charles

AU - Kral, Brian G.

AU - Loos, Ruth J.F.

AU - Lutz, Sharon M.

AU - Manson, Jo Ann E.

AU - Martin, Lisa W.

AU - Mitchell, Braxton D.

AU - Nassir, Rami

AU - Palmer, Nicholette D.

AU - Post, Wendy S.

AU - Preuss, Michael H.

AU - Psaty, Bruce M.

AU - Raffield, Laura M.

AU - Regan, Elizabeth A.

AU - Rich, Stephen S.

AU - Smith, Jennifer A.

AU - Taylor, Kent D.

AU - Yanek, Lisa R.

AU - Young, Kendra A.

AU - Zhao, Snow Xueyan

AU - Yang, Ivana

AU - Weng, Lu Chen

PY - 2024/12

Y1 - 2024/12

N2 - Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

AB - Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

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Rare variant contribution to the heritability of coronary artery disease

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