Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness

Abdel Abdellaoui, Jorien L Treur, Michel G Nivard, Hill Fung Ip, Matthijs van der Zee, Bart M L Baselmans, Jouke Jan Hottenga, Gonneke Willemsen, Karin J H Verweij, Dorret I Boomsma, 23Andme Research Team

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. While the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. While it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition towards loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study (GWAS) meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with electronic health record data to conduct a PheWAS with. A genetic predisposition towards loneliness was associated with cardiovascular, psychiatric, and metabolic disorders, and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

Original languageEnglish
Pages (from-to)3853-3865
Number of pages13
JournalHuman Molecular Genetics
Volume28
Issue number22
DOIs
Publication statusPublished - 15 Nov 2019

Bibliographical note

© The Author(s) 2019. Published by Oxford University Press.

Funding

The National Institutes of Health (NIH, R01AG033590 to JC); the Royal Netherlands Academy of Science Professor Award (PAH/6635 to NTR: DIB). Data collection and genotyping in NTR by the Netherlands Organization for Scientific Research (904- 61-090, 85-10-002, 904-61-193, 480-04-004, 400-05-717, Spi-56- 464-14192 and 480-15-001/674); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI - NL, 184.021.007 and 184.033.111); the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH, R01D0042157-01A); the NIMH Grand Opportunity grants (1RC2MH089951-01 and 1RC2 MH089995-01). A Rubicon grant from the Netherlands Organization for Scientific Research (NWO; grant number 446-16-009 to J.L.T.); NIMH (grant 5R01MH113362-02 to L.K.D.); NIH training grant (2T32GM080178 to J.M.S). The Frontiers of Innovation Scholars Program (FISP; #3-P3029 to S.S.-R.); the Interdisciplinary Research Fellowship in NeuroAIDS (IRFN; MH081482); a pilot award from DA037844 and 2018 NARSAD Young Investigator Grant (27676); the California Tobacco-Related Disease Research Program (TRDRP; Grant Number 28IR-0070 to S.S.-R. and A.A.P.); Institutional funding (the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR000445 from NCATS/NIH to Medical Center's BioVU); NIH (additional funding through grants P50GM115305 and U19HL065962); Part of the computations for this paper was performed on Cartesius (grant 'Population scale genetic analysis'; NWO rekentijd: 16332). The National Institutes of Health (NIH, R01AG033590 to JC); the Royal Netherlands Academy of Science Professor Award (PAH/6635 to NTR: DIB). Data collection and genotyping in NTR by the Netherlands Organization for Scientific Research (904-61-090, 85-10-002, 904-61-193, 480-04-004, 400-05-717, Spi-56-464-14192 and 480-15-001/674); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI – NL, 184.021.007 and 184.033.111); the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH, R01D0042157-01A); the NIMH Grand Opportunity grants (1RC2MH089951-01 and 1RC2 MH089995-01). A Rubicon grant from the Netherlands Organization for Scientific Research (NWO; grant number 446-16-009 to J.L.T.); NIMH (grant 5R01MH113362-02 to L.K.D.); NIH training grant (2T32GM080178 to J.M.S). The Frontiers of Innovation Scholars Program (FISP; #3-P3029 to S.S.-R.); the Interdisciplinary Research Fellowship in NeuroAIDS (IRFN; MH081482); a pilot award from DA037844 and 2018 NARSAD Young Investigator Grant (27676); the California Tobacco-Related Disease Research Program (TRDRP; Grant Number 28IR-0070 to S.S.-R. and A.A.P.); Institutional funding (the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR000445 from NCATS/NIH to Medical Center’s BioVU); NIH (additional funding through grants P50GM115305 and U19HL065962); Part of the computations for this paper was performed on Cartesius (grant ‘Population scale genetic analysis’; NWO rekentijd: 16332).

FundersFunder number
Avera Institute for Human Genetics
BBMRI184.033.111, 184.021.007
Biobanking and Biomolecular Resources Research Infrastructure
California Tobacco-Related Disease Research Program
NCATS/NIH
Netherlands Organization for Scientific Research
Royal Netherlands Academy of SciencePAH/6635
National Institutes of HealthR01AG033590, R01D0042157-01A
National Institute of Mental Health1RC2MH089951-01, 1RC2 MH089995-01
National Institute of General Medical SciencesT32GM080178
Tobacco-Related Disease Research Program28IR-0070, UL1TR000445, 1S10RR025141-01
National Center for Advancing Translational SciencesU19HL065962, 16332, P50GM115305
National Alliance for Research on Schizophrenia and Depression27676
Nederlandse Organisatie voor Wetenschappelijk Onderzoek2T32GM080178, 480-04-004, 85-10-002, 904-61-090, 400-05-717, DA037844, Spi-56-464-14192, 904-61-193, 5R01MH113362-02, 446-16-009, 480-15-001/674, MH081482

    Cohort Studies

    • Netherlands Twin Register (NTR)

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