Inference of Causal Relationships Between Genetic Risk Factors for Cardiometabolic Phenotypes and Female-Specific Health Conditions

for the Regeneron Genetics Center

doi:10.1161/JAHA.121.026561

Inference of Causal Relationships Between Genetic Risk Factors for Cardiometabolic Phenotypes and Female-Specific Health Conditions

for the Regeneron Genetics Center

Preventive Medicine

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

10 Scopus citations

Abstract

BACKGROUND: Cardiometabolic diseases are highly comorbid, but their relationship with female-specific or overwhelmingly female-predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross-trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to women. METHODS AND RESULTS: Using electronic health record data from 71 008 ancestrally diverse women, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index, coronary artery disease, type 2 diabetes, and hypertension) by performing 4 analyses: (1) cross-trait genetic correlation analyses to compare genetic architecture, (2) polygenic risk score–based association tests to characterize shared genetic effects on disease risk, (3) Mendelian randomization for significant associations to assess cross-trait causal relationships, and (4) chronology analyses to visualize the timeline of events unique to groups of women with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. We observed 27 significant associations between cardiometabolic polygenic scores and obstetrical/gynecological conditions (body mass index and endometrial cancer, body mass index and polycystic ovarian syndrome, type 2 diabetes and gestational diabetes, type 2 diabetes and polycystic ovarian syndrome). Mendelian randomization analysis provided additional evidence of independent causal effects. We also identified an inverse association between coronary artery disease and breast cancer. High cardiometabolic polygenic scores were associated with early development of polycystic ovarian syndrome and gestational hypertension. CONCLUSIONS: We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female-specific health conditions.

Original language	English (US)
Article number	e026561
Journal	Journal of the American Heart Association
Volume	12
Issue number	5
DOIs	https://doi.org/10.1161/JAHA.121.026561
State	Published - Mar 7 2023

Funding

The eMERGE network was initiated and funded by National Human Genome Research Institute through the following grants: Phase IV: U01HG011172 (Cincinnati Children’s Hospital Medical Center), U01HG011175 (Children’s Hospital of Philadelphia), U01HG008680 (Columbia University), U01HG011176 (Icahn School of Medicine at Mount Sinai), U01HG008685 (Mass General Brigham), U01HG006379 (Mayo Clinic), U01HG011169 (Northwestern University), U01HG011167 (University of Alabama at Birmingham), U01HG008657 (University of Washington Medical Center, Seattle), U01HG011181 (Vanderbilt University Medical Center), U01HG011166 (Vanderbilt University Medical Center serving as the Coordinating Center). Phase III: U01HG8657 (Kaiser Permanente Washington/University of Washington Medical Center), U01HG8685 (Brigham and Women’s Hospital), U01HG8672 (Vanderbilt University Medical Center), U01HG8666 (Cincinnati Children’s Hospital Medical Center), U01HG6379 (Mayo Clinic), U01HG8679 (Geisinger Clinic), U01HG8680 (Columbia University Health Sciences), U01HG8684 (Children’s Hospital of Philadelphia), U01HG8673 (Northwestern University), U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG8676 (Partners Healthcare/Broad Institute), and U01HG8664 (Baylor College of Medicine). The eMERGE network was initiated and funded by National Human Genome Research Institute through the following grants: Phase IV: U01HG011172 (Cincinnati Children’s Hospital Medical Center), U01HG011175 (Children’s Hospital of Philadelphia), U01HG008680 (Columbia University), U01HG011176 (Icahn School of Medicine at Mount Sinai), U01HG008685 (Mass General Brigham), U01HG006379 (Mayo Clinic), U01HG011169 (Northwestern University), U01HG011167 (University of Alabama at Birmingham), U01HG008657 (University of Washington Medical Center,

Keywords

Mendelian randomization
cardiometabolic diseases
female health conditions
genomic burden
polygenic risk scores

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/JAHA.121.026561

Cite this

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title = "Inference of Causal Relationships Between Genetic Risk Factors for Cardiometabolic Phenotypes and Female-Specific Health Conditions",

abstract = "BACKGROUND: Cardiometabolic diseases are highly comorbid, but their relationship with female-specific or overwhelmingly female-predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross-trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to women. METHODS AND RESULTS: Using electronic health record data from 71 008 ancestrally diverse women, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index, coronary artery disease, type 2 diabetes, and hypertension) by performing 4 analyses: (1) cross-trait genetic correlation analyses to compare genetic architecture, (2) polygenic risk score–based association tests to characterize shared genetic effects on disease risk, (3) Mendelian randomization for significant associations to assess cross-trait causal relationships, and (4) chronology analyses to visualize the timeline of events unique to groups of women with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. We observed 27 significant associations between cardiometabolic polygenic scores and obstetrical/gynecological conditions (body mass index and endometrial cancer, body mass index and polycystic ovarian syndrome, type 2 diabetes and gestational diabetes, type 2 diabetes and polycystic ovarian syndrome). Mendelian randomization analysis provided additional evidence of independent causal effects. We also identified an inverse association between coronary artery disease and breast cancer. High cardiometabolic polygenic scores were associated with early development of polycystic ovarian syndrome and gestational hypertension. CONCLUSIONS: We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female-specific health conditions.",

keywords = "Mendelian randomization, cardiometabolic diseases, female health conditions, genomic burden, polygenic risk scores",

author = "\{for the Regeneron Genetics Center\} and Brenda Xiao and Edwards, \{Digna R.Velez\} and Anastasia Lucas and Theodore Drivas and Kathryn Gray and Brendan Keating and Chunhua Weng and Jarvik, \{Gail P.\} and Hakon Hakonarson and Leah Kottyan and Noemie Elhadad and Wei, \{Wei Qi\} and Yuan Luo and Dokyoon Kim and Marylyn Ritchie and Verma, \{Shefali Setia\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.",

year = "2023",

month = mar,

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doi = "10.1161/JAHA.121.026561",

language = "English (US)",

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journal = "Journal of the American Heart Association",

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AU - for the Regeneron Genetics Center

AU - Xiao, Brenda

AU - Edwards, Digna R.Velez

AU - Lucas, Anastasia

AU - Drivas, Theodore

AU - Gray, Kathryn

AU - Keating, Brendan

AU - Weng, Chunhua

AU - Jarvik, Gail P.

AU - Hakonarson, Hakon

AU - Kottyan, Leah

AU - Elhadad, Noemie

AU - Wei, Wei Qi

AU - Luo, Yuan

AU - Kim, Dokyoon

AU - Ritchie, Marylyn

AU - Verma, Shefali Setia

PY - 2023/3/7

Y1 - 2023/3/7

N2 - BACKGROUND: Cardiometabolic diseases are highly comorbid, but their relationship with female-specific or overwhelmingly female-predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross-trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to women. METHODS AND RESULTS: Using electronic health record data from 71 008 ancestrally diverse women, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index, coronary artery disease, type 2 diabetes, and hypertension) by performing 4 analyses: (1) cross-trait genetic correlation analyses to compare genetic architecture, (2) polygenic risk score–based association tests to characterize shared genetic effects on disease risk, (3) Mendelian randomization for significant associations to assess cross-trait causal relationships, and (4) chronology analyses to visualize the timeline of events unique to groups of women with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. We observed 27 significant associations between cardiometabolic polygenic scores and obstetrical/gynecological conditions (body mass index and endometrial cancer, body mass index and polycystic ovarian syndrome, type 2 diabetes and gestational diabetes, type 2 diabetes and polycystic ovarian syndrome). Mendelian randomization analysis provided additional evidence of independent causal effects. We also identified an inverse association between coronary artery disease and breast cancer. High cardiometabolic polygenic scores were associated with early development of polycystic ovarian syndrome and gestational hypertension. CONCLUSIONS: We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female-specific health conditions.

AB - BACKGROUND: Cardiometabolic diseases are highly comorbid, but their relationship with female-specific or overwhelmingly female-predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross-trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to women. METHODS AND RESULTS: Using electronic health record data from 71 008 ancestrally diverse women, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index, coronary artery disease, type 2 diabetes, and hypertension) by performing 4 analyses: (1) cross-trait genetic correlation analyses to compare genetic architecture, (2) polygenic risk score–based association tests to characterize shared genetic effects on disease risk, (3) Mendelian randomization for significant associations to assess cross-trait causal relationships, and (4) chronology analyses to visualize the timeline of events unique to groups of women with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. We observed 27 significant associations between cardiometabolic polygenic scores and obstetrical/gynecological conditions (body mass index and endometrial cancer, body mass index and polycystic ovarian syndrome, type 2 diabetes and gestational diabetes, type 2 diabetes and polycystic ovarian syndrome). Mendelian randomization analysis provided additional evidence of independent causal effects. We also identified an inverse association between coronary artery disease and breast cancer. High cardiometabolic polygenic scores were associated with early development of polycystic ovarian syndrome and gestational hypertension. CONCLUSIONS: We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female-specific health conditions.

KW - Mendelian randomization

KW - cardiometabolic diseases

KW - female health conditions

KW - genomic burden

KW - polygenic risk scores

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Inference of Causal Relationships Between Genetic Risk Factors for Cardiometabolic Phenotypes and Female-Specific Health Conditions

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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