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Hum Mol Genet. 2019 Nov 15;28(22):3853-3865. doi: 10.1093/hmg/ddz219.

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

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Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Vanderbilt Genetics Institute, Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
School of Experimental Psychology, University of Bristol, Bristol, UK.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
23andMe, Inc., Mountain View, CA, USA.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Translational Epidemiology, Faculty Science, Leiden University, Leiden, The Netherlands.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Rotterdam, The Netherlands.
Center for Cognitive and Social Neuroscience, Department of Psychology, The University of Chicago, Chicago, Illinois, USA.


Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although 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. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study 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 EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the 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.

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