Genome-Wide Association Study of Loneliness Demonstrates a Role for Common Variation

Abstract

Loneliness is a complex biological trait that has been associated with numerous negative health outcomes. The measurement and environmental determinants of loneliness are well understood, but its genetic basis is not. Previous studies have estimated the heritability of loneliness between 37 and 55% using twins and family-based approaches, and have explored the role of specific candidate genes. We used genotypic and phenotypic data from 10 760 individuals aged ⩾ 50 years that were collected by the Health and Retirement Study (HRS) to perform the first genome-wide association study of loneliness. No associations reached genome-wide significance (p45 × 10 − 8 ). Furthermore, none of the previously published associations between variants within candidate genes (BDNF, OXTR, RORA, GRM8, CHRNA4, IL-1A, CRHR1, MTHFR, DRD2, APOE) and loneliness were replicated (p40.05), despite our much larger sample size. We estimated the chip heritability of loneliness and examined coheritability between loneliness and several personality and psychiatric traits. Our estimates of chip heritability (14-27%) support a role for common genetic variation. We identified strong genetic correlations between loneliness, neuroticism, and a scale of 'depressive symptoms.' We also identified weaker evidence for coheritability with extraversion, schizophrenia, bipolar disorder, and major depressive disorder. We conclude that loneliness, as defined in this study, is a modestly heritable trait that has a highly polygenic genetic architecture. The coheritability between loneliness and neuroticism may reflect the role of negative affectivity that is common to both traits. Our results also reflect the value of studies that probe the common genetic basis of salutary social bonds and clinically defined psychiatric disorders.

Predicting loneliness with polygenic scores of social, psychological and psychiatric traits

“…They found a significant association only with neuroticism and depressive symptoms. The reason that our strongest predictors, MDD, did not reach significance in their study was likely due to the differences in the sample sizes of the MDD GWASs: 18 759 in Gao et al 24 and over 160 000 in our study. The power to detect associations with additional traits that did not reach significance in their analyses (schizophrenia and bipolar disorder) may be due to our larger sample size and the use of LDpred to construct polygenic scores, which increases power by optimizing the effect size estimates of individual SNPs by incorporating the genome-wide LD structure.…”

“…Gao et al 24 investigated the association between loneliness in approximately 7000 unrelated individuals from the HRS and polygenic scores for 6 traits: neuroticism, extraversion, schizophrenia, bipolar disorder, MDD and depressive symptoms. They found a significant association only with neuroticism and depressive symptoms.…”

Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

“…Multiple additional SNPs at KCNMB2 have been reported as strong signals in previous GWAS of other disorders, including SCZ and bipolar disorder (e.g., rs2054399, P = 1 × 10 −06 ) [Bergen et al, ]. In addition, the top signals, rs7274133, and rs852099 at PCSK2 are in perfect LD ( D ′ = 1) with rs78649567, which has been associated with loneliness ( P = 3 × 10 −06 ) [Gao et al, ], and with rs11696277, which has been associated with gut microbiome composition ( P = 1 × 10 −06 ) [Davenport et al, ], a condition altered in individuals with ASD [Li, Hu, Ou, & K, ]. Moreover, rs310619 at EEF1A2 (OR = 2.40; P = 7.44 × 10 −05 ) was associated with autism and had a cis ‐effect on the cerebellum (NES = 0.128; P = 8.9 × 10 −04 ) in the GTEx data set (Table S3).…”

A SNP, Gene, and Polygenic Risk Score Approach of Oxytocin‐Vasopressin Genes in Adolescents’ Loneliness

“…Other significant associations for SNP rs75775 have been observed for autism and related social characteristics (Wang et al., ) and, more interestingly, this SNP has also been associated with prosocial behavior (Apicella et al., ), a trait that has been described in relation to loneliness (e.g., loneliness could either decrease or increase prosocial behavior due to enhanced self‐focus or the urge to restore relationships (Spithoven, Vanhalst, Lodder, Bijttebier, & Goossens, ; Twenge, Baumeister, DeWall, Ciarocco, & Bartels, ; Woodhouse, Dykas, & Cassidy, ). This SNP was not significantly associated with loneliness in the GWAS comprising adults aged 50 and over (Gao et al., ). For the other significant SNPs in our study (rs918316 and rs6793234), no previous associations have been documented.…”

“…However, a recent genome‐wide association study (GWAS) of loneliness did not detect genome‐wide significant associations for variants in the OXTR , AVPR1A , AVPR1B, and OXT genes, nor any other gene (Gao et al., ). Although the sample size of over 10,000 participants is quite large, the power was still insufficient to detect variants genome‐wide that are significantly associated with loneliness.…”