Genetic contributions to self-reported tiredness

Abstract

Self-reported tiredness and low energy, often called fatigue, are associated with poorer physical and mental health. Twin studies have indicated that this has a heritability between 6 and 50%. In the UK Biobank sample (N=108 976), we carried out a genome-wide association study (GWAS) of responses to the question, 'Over the last two weeks, how often have you felt tired or had little energy?' Univariate GCTA-GREML found that the proportion of variance explained by all common single-nucleotide polymorphisms for this tiredness question was 8.4% (s.e.=0.6%). GWAS identified one genome-wide significant hit (Affymetrix id 1:64178756_C_T; P=1.36 × 10^-11). Linkage disequilibrium score regression and polygenic profile score analyses were used to test for shared genetic aetiology between tiredness and up to 29 physical and mental health traits from GWAS consortia. Significant genetic correlations were identified between tiredness and body mass index (BMI), C-reactive protein, high-density lipoprotein (HDL) cholesterol, forced expiratory volume, grip strength, HbA1c, longevity, obesity, self-rated health, smoking status, triglycerides, type 2 diabetes, waist-hip ratio, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, neuroticism, schizophrenia and verbal-numerical reasoning (absolute r_g effect sizes between 0.02 and 0.78). Significant associations were identified between tiredness phenotypic scores and polygenic profile scores for BMI, HDL cholesterol, low-density lipoprotein cholesterol, coronary artery disease, C-reactive protein, HbA1c, height, obesity, smoking status, triglycerides, type 2 diabetes, waist-hip ratio, childhood cognitive ability, neuroticism, bipolar disorder, major depressive disorder and schizophrenia (standardised β's had absolute values<0.03). These results suggest that tiredness is a partly heritable, heterogeneous and complex phenomenon that is phenotypically and genetically associated with affective, cognitive, personality and physiological processes.

Figure 1

Flow diagram of participant selection.

Figure 2

(a) Manhattan and (b) Q–Q plot of P-values of the SNP-based association analysis of tiredness (responses to the question, ‘Over the past two weeks, how often have you felt tired or had little energy?’). The red line on the Manhattan plot indicates the threshold for genome-wide significance (P<5 × 10⁻⁸); the grey line on the Manhattan plot indicates the threshold for suggestive significance (P<1 × 10⁻⁵). SNP, single-nucleotide polymorphism.

Figure 3

Barplot of genetic correlations (s.e.) calculated using LD regression between tiredness in UK Biobank and mental and physical health measures from GWAS consortia. *P<0.0281. ADHD, attention deficit hyperactivity disorder; BMI, body mass index; GWAS, genome-wide association study; HDL, high-density lipoprotein; LD, linkage disequilibrium; LDL, low-density lipoprotein.

Figure 4

Age- and sex-stratified heritability estimates with s.e.’s for tiredness. SNP, single-nucleotide polymorphism.