Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

Jessica Dennis; Julia Sealock; Rebecca T Levinson; Eric Farber-Eger; Jacob Franco; Sarah Fong; Peter Straub; Donald Hucks; Wen-Liang Song; MacRae F Linton; Pierre Fontanillas; Sarah L Elson; Douglas Ruderfer; Abdel Abdellaoui; Sandra Sanchez-Roige; Abraham A Palmer; Dorret I Boomsma; Nancy J Cox; Guanhua Chen; Jonathan D Mosley; Quinn S Wells; Lea K Davis

doi:10.1038/s41380-019-0614-y

Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

Jessica Dennis, Julia Sealock, Rebecca T Levinson, Eric Farber-Eger, Jacob Franco, Sarah Fong, Peter Straub, Donald Hucks, Wen-Liang Song, MacRae F Linton, Pierre Fontanillas, Sarah L Elson, Douglas Ruderfer, Abdel Abdellaoui, Sandra Sanchez-Roige, Abraham A Palmer, Dorret I Boomsma, Nancy J Cox, Guanhua Chen, Jonathan D MosleyQuinn S Wells, Lea K Davis

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10-4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

Original language	English
Pages (from-to)	4254-4264
Number of pages	11
Journal	Molecular Psychiatry
Volume	26
Issue number	8
Early online date	3 Dec 2019
DOIs	https://doi.org/10.1038/s41380-019-0614-y
Publication status	Published - Aug 2021

Funding

Acknowledgements JD is supported by the Canadian Institutes of Health Research (award MFE-142936). RTL is supported by AHA grant 17SFRN33520017 and NIH 1R01HL140074-01. MFL is supported by PO1HL116263 and R01HL127173. SS-R is supported by the Frontiers of Innovation Scholars Program (FISP; #3-P3029), the Interdisciplinary Research Fellowship in NeuroAIDS (IRFN; MH081482), and a pilot award from DA037844. SS-R and AAP are supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; Grant nos. 28IR-0070 and T29KT0526). AAP is supported by P50DA037844. AA and DIB acknowledge NIH R37 AG033590-08 grant to J Cacioppo. Support for NJC was provided by R01MH113362, U54MD010722, and U01HG009086. GC is supported by NIH UL1TR000427. JDM is supported by AHA grant 16FTF30130005. LKD is supported by NIH 1R01MH118233-01 and 1R56MH120736-01. This project was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. The datasets used for this project were obtained from Vanderbilt University Medical Center’s Synthetic Derivative, which is supported by numerous sources: institutional funding, private agencies, and federal grants. The project described was supported by the National Center for Research Resources, Grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Data on coronary artery disease/myocardial infarction have been contributed by CAR-DIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG. The authors thank the staff and participants of the ARIC study for their contributions. ARIC is supported by NHLBI contracts (HHSN268201100005C, HHSN26820 1100006C, HHSN268201100007C, HHSN268201100008C, HHSN2 68201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). ARIC/GENEVA was supported by NHGRI grant U01HG004402 (E. Boerwinkle).

Funders	Funder number
National Institutes of Health	1R01HL140074-01, 3-P3029, PO1HL116263, MH081482
National Institute of Mental Health	1R56MH120736-01, 1R01MH118233-01
National Institute on Drug Abuse	P50DA037844
National Heart, Lung, and Blood Institute	HHSN268201100005C, R01HL127173
National Human Genome Research Institute	U01HG004402
National Center for Research Resources	UL1 RR024975-01
Tobacco-Related Disease Research Program	R37 AG033590-08, 28IR-0070, 16FTF30130005, T29KT0526
National Center for Advancing Translational Sciences	2 UL1 TR000445-06, UL1TR000427
Vanderbilt University Medical Center
Canadian Institutes of Health Research
CIHR Skin Research Training Centre	MFE-142936
Animal Health Australia	17SFRN33520017

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

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Dennis, J., Sealock, J., Levinson, R. T., Farber-Eger, E., Franco, J., Fong, S., Straub, P., Hucks, D., Song, W.-L., Linton, M. F., Fontanillas, P., Elson, S. L., Ruderfer, D., Abdellaoui, A., Sanchez-Roige, S., Palmer, A. A., Boomsma, D. I., Cox, N. J., Chen, G., ... Davis, L. K. (2021). Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease. Molecular Psychiatry, 26(8), 4254-4264. https://doi.org/10.1038/s41380-019-0614-y

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abstract = "Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10-4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.",

author = "Jessica Dennis and Julia Sealock and Levinson, {Rebecca T} and Eric Farber-Eger and Jacob Franco and Sarah Fong and Peter Straub and Donald Hucks and Wen-Liang Song and Linton, {MacRae F} and Pierre Fontanillas and Elson, {Sarah L} and Douglas Ruderfer and Abdel Abdellaoui and Sandra Sanchez-Roige and Palmer, {Abraham A} and Boomsma, {Dorret I} and Cox, {Nancy J} and Guanhua Chen and Mosley, {Jonathan D} and Wells, {Quinn S} and Davis, {Lea K}",

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doi = "10.1038/s41380-019-0614-y",

language = "English",

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Dennis, J, Sealock, J, Levinson, RT, Farber-Eger, E, Franco, J, Fong, S, Straub, P, Hucks, D, Song, W-L, Linton, MF, Fontanillas, P, Elson, SL, Ruderfer, D, Abdellaoui, A, Sanchez-Roige, S, Palmer, AA, Boomsma, DI, Cox, NJ, Chen, G, Mosley, JD, Wells, QS & Davis, LK 2021, 'Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease', Molecular Psychiatry, vol. 26, no. 8, pp. 4254-4264. https://doi.org/10.1038/s41380-019-0614-y

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T1 - Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

AU - Dennis, Jessica

AU - Sealock, Julia

AU - Levinson, Rebecca T

AU - Farber-Eger, Eric

AU - Franco, Jacob

AU - Fong, Sarah

AU - Straub, Peter

AU - Hucks, Donald

AU - Song, Wen-Liang

AU - Linton, MacRae F

AU - Fontanillas, Pierre

AU - Elson, Sarah L

AU - Ruderfer, Douglas

AU - Abdellaoui, Abdel

AU - Sanchez-Roige, Sandra

AU - Palmer, Abraham A

AU - Boomsma, Dorret I

AU - Cox, Nancy J

AU - Chen, Guanhua

AU - Mosley, Jonathan D

AU - Wells, Quinn S

AU - Davis, Lea K

PY - 2021/8

Y1 - 2021/8

N2 - Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10-4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

AB - Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10-4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

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Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

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UN SDGs

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