An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids

Xin Geng; Marguerite R. Irvin; Bertha Hidalgo; Stella Aslibekyan; Vinodh Srinivasasainagendra; Ping An; Alexis C. Frazier-Wood; Hemant K. Tiwari; Tushar Dave; Kathleen Ryan; Jose M. Ordovas; Robert J. Straka; Mary F. Feitosa; Paul N. Hopkins; Ingrid Borecki; Michael A. Province; Braxton D. Mitchell; Donna K. Arnett; Degui Zhi

doi:10.3389/fgene.2019.00158

An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids

Xin Geng, Marguerite R. Irvin, Bertha Hidalgo, Stella Aslibekyan, Vinodh Srinivasasainagendra, Ping An, Alexis C. Frazier-Wood, Hemant K. Tiwari, Tushar Dave, Kathleen Ryan, Jose M. Ordovas, Robert J. Straka, Mary F. Feitosa, Paul N. Hopkins, Ingrid Borecki, Michael A. Province, Braxton D. Mitchell, Donna K. Arnett, Degui Zhi

College of Public Health

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

2 Scopus citations

Abstract

Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 (P = 1.77E-07) and SLCO2A1 (P = 7.18E-07) and triglycerides, as well as between POT1 (P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P-values of 0.04 (ITGA7), 0.08 (SLCO2A1), and 0.02 (POT1). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides (P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.

Original language	English
Article number	158
Journal	Frontiers in Genetics
Volume	10
Issue number	feburay
DOIs	https://doi.org/10.3389/fgene.2019.00158
State	Published - 2019

Bibliographical note

Publisher Copyright:
© 2019 Geng, Irvin, Hidalgo, Aslibekyan, Srinivasasainagendra, An, Frazier-Wood, Tiwari, Dave, Ryan, Ordovas, Straka, Feitosa, Hopkins, Borecki, Province, Mitchell, Arnett and Zhi.

Funding

The GOLDN study has been funded by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) Grants U01HL072524 and R01HL091357. SA is additionally funded by NHLBI K01 HL136700 and JO by the U.S. Department of Agriculture, under agreement Nos. 8050-51000-098-00D and USDA-AFRI 2017-67017-26719. HyperGEN and GENOA have been funded by NIH R01HL055673 and U01HL075572. The HAPI Heart Study was supported by NIH grants U01 HL072515 and P30 DK072488. Whole genome sequencing of Amish subjects was provided by the Trans-Omics for Precision Medicine program through the National Heart, Lung and Blood Institute (NHLBI) and funded by 3R01HL121007-01S1, 3R01HL-117626-02S1, and 3R01HL-120393-02S1. XG and DZ are partially supported by Agriculture and Food Research Initiative Competitive Grant no. 2015-67015-22975 from the USDA National Institute of Food and Agriculture, and USDA Aquaculture Research Program Competitive Grant no. 2014-70007-22395.

Funders	Funder number
USDA-NIFA-AFRI	P30 DK072488, R01HL055673, U01 HL072515, U01HL075572, 2017-67017-26719
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)	3R01HL121007-01S1, R01HL091357, U01HL072524, K01 HL136700, 3R01HL-117626-02S1, 3R01HL-120393-02S1, 2015-67015-22975
U.S. Department of Agriculture	8050-51000-098-00D, 2014-70007-22395
National Institute of Food and Agriculture

Keywords

Cholesterol
Epidemiology
Genetics
HDL
LDL
Rare variant
Triglyceride
Whole exome sequencing

ASJC Scopus subject areas

Molecular Medicine
Genetics
Genetics(clinical)

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10.3389/fgene.2019.00158

Cite this

Geng, X., Irvin, M. R., Hidalgo, B., Aslibekyan, S., Srinivasasainagendra, V., An, P., Frazier-Wood, A. C., Tiwari, H. K., Dave, T., Ryan, K., Ordovas, J. M., Straka, R. J., Feitosa, M. F., Hopkins, P. N., Borecki, I., Province, M. A., Mitchell, B. D., Arnett, D. K., & Zhi, D. (2019). An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids. Frontiers in Genetics, 10(feburay), Article 158. https://doi.org/10.3389/fgene.2019.00158

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title = "An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids",

abstract = "Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 (P = 1.77E-07) and SLCO2A1 (P = 7.18E-07) and triglycerides, as well as between POT1 (P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P-values of 0.04 (ITGA7), 0.08 (SLCO2A1), and 0.02 (POT1). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides (P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.",

keywords = "Cholesterol, Epidemiology, Genetics, HDL, LDL, Rare variant, Triglyceride, Whole exome sequencing",

author = "Xin Geng and Irvin, {Marguerite R.} and Bertha Hidalgo and Stella Aslibekyan and Vinodh Srinivasasainagendra and Ping An and Frazier-Wood, {Alexis C.} and Tiwari, {Hemant K.} and Tushar Dave and Kathleen Ryan and Ordovas, {Jose M.} and Straka, {Robert J.} and Feitosa, {Mary F.} and Hopkins, {Paul N.} and Ingrid Borecki and Province, {Michael A.} and Mitchell, {Braxton D.} and Arnett, {Donna K.} and Degui Zhi",

note = "Publisher Copyright: {\textcopyright} 2019 Geng, Irvin, Hidalgo, Aslibekyan, Srinivasasainagendra, An, Frazier-Wood, Tiwari, Dave, Ryan, Ordovas, Straka, Feitosa, Hopkins, Borecki, Province, Mitchell, Arnett and Zhi.",

year = "2019",

doi = "10.3389/fgene.2019.00158",

language = "English",

volume = "10",

number = "feburay",

}

Geng, X, Irvin, MR, Hidalgo, B, Aslibekyan, S, Srinivasasainagendra, V, An, P, Frazier-Wood, AC, Tiwari, HK, Dave, T, Ryan, K, Ordovas, JM, Straka, RJ, Feitosa, MF, Hopkins, PN, Borecki, I, Province, MA, Mitchell, BD, Arnett, DK & Zhi, D 2019, 'An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids', Frontiers in Genetics, vol. 10, no. feburay, 158. https://doi.org/10.3389/fgene.2019.00158

TY - JOUR

T1 - An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids

AU - Geng, Xin

AU - Irvin, Marguerite R.

AU - Hidalgo, Bertha

AU - Aslibekyan, Stella

AU - Srinivasasainagendra, Vinodh

AU - An, Ping

AU - Frazier-Wood, Alexis C.

AU - Tiwari, Hemant K.

AU - Dave, Tushar

AU - Ryan, Kathleen

AU - Ordovas, Jose M.

AU - Straka, Robert J.

AU - Feitosa, Mary F.

AU - Hopkins, Paul N.

AU - Borecki, Ingrid

AU - Province, Michael A.

AU - Mitchell, Braxton D.

AU - Arnett, Donna K.

AU - Zhi, Degui

N1 - Publisher Copyright: © 2019 Geng, Irvin, Hidalgo, Aslibekyan, Srinivasasainagendra, An, Frazier-Wood, Tiwari, Dave, Ryan, Ordovas, Straka, Feitosa, Hopkins, Borecki, Province, Mitchell, Arnett and Zhi.

PY - 2019

Y1 - 2019

N2 - Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 (P = 1.77E-07) and SLCO2A1 (P = 7.18E-07) and triglycerides, as well as between POT1 (P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P-values of 0.04 (ITGA7), 0.08 (SLCO2A1), and 0.02 (POT1). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides (P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.

AB - Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 (P = 1.77E-07) and SLCO2A1 (P = 7.18E-07) and triglycerides, as well as between POT1 (P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P-values of 0.04 (ITGA7), 0.08 (SLCO2A1), and 0.02 (POT1). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides (P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.

KW - Cholesterol

KW - Epidemiology

KW - Genetics

KW - HDL

KW - LDL

KW - Rare variant

KW - Triglyceride

KW - Whole exome sequencing

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U2 - 10.3389/fgene.2019.00158

DO - 10.3389/fgene.2019.00158

M3 - Article

AN - SCOPUS:85065816821

SN - 1664-8021

VL - 10

JO - Frontiers in Genetics

JF - Frontiers in Genetics

IS - feburay

M1 - 158

ER -

An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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