Fatigue is characterized by self-reported tiredness and low energy. Obvious behaviors such as sleeping less than the National Sleep Foundation recommended 7-9 hours a night, eating nutrient-poor foods that cause spikes in blood sugar, or excessive exercise without adequate rest and recovery can all lead to fatigue. Tiredness is a common problem among our population, the University of Edinburgh’s Department of Psychology and Division of Psychiatry reports a fatigue rate of 37.9% from a large survey of adults aged 51 years and over. These respondents indicated feeling tired for a 2-week period. However, recent studies have shown that genetic factors, not just environmental factors, may contribute to self-reported tiredness. This should not be ignored since some aspects of our tiredness may be out of our control; it should be recognized that simple behavioral changes may not completely resolve the issue of fatigue itself, but those predisposed can make choices to accommodate this trouble. A study conducted by Deary and colleagues attempts to determine the contributors to fatigue on the genetic level. In this study, a genome-wide analysis of 108,976 UK Biobank participants with genotypic data was conducted. The UK Biobank is a resource used to identify determinants of human diseases in middle-aged and older individuals. It contains 502,655 people between 37-73 years old who were assessed for baseline data such as cognitive testing, personality self-report, and physical and mental health measures. In this study, the researchers investigated how the participants of the UK Biobank responded to the question, “Over the last two weeks, how often have you felt tired or had little energy?” In response, 47% of individuals answered “not at all,” 41% answered “several days,” 6% answered “more than half the days,” and 6% responded “nearly every day.” Phenotypic correlations revealed that more tired individuals seemed to have lower grip strength, lower lung function, poorer self-rated health, lower scores for verbal-numerical reasoning, shorter stature, higher BMI, and higher scores for neuroticism. According to the genome-wide association study (GWAS), single-nucleotide polymorphisms (single base variations within the genome) related to fatigue were found in genes on chromosomes 1 and 17. These genes relate to levels of the hormone resistin, associated with insulin resistance, inflammation, and risk of both type 2 diabetes and cardiovascular disease; genes for a carrier protein needed for lipid and lipoprotein metabolism; and genes for an enzymatic subunit important in brain development and spermatogenesis. Five genes—DRD2, PRRC2C, C3orf84, ANO10, and ASXL3—were identified from a gene-based association analysis and attained genome-wide significance (2.9 x 10-7, 1.43 x 10-6, 1.45 x 10-6, 1.52 x 10-6, and 2.67 x 10-6, respectively) for fatigue after correcting data for multiple comparisons. Mutations in these genes have been associated with psychiatric illnesses, lung cancer, cerebellar ataxias, intellectual disability, feeding problems, and distinctive facial features. This range of factors- affective, cognitive, behavioral, and physical- are genetically linked with tiredness and confirms the heterogeneity of fatigue. In general, there is a genetic link between tiredness and tendency to poor health as demonstrated by the genetic association between fatigue and longevity. The association between genetic variants associated with tiredness and multiple physical and mental health-related traits were tested. Researchers found that tiredness and BMI, C-reactive protein (involved in inflammation), glycated hemoglobin, obesity, smoking status, triglycerides, type 2 diabetes, waist-hip ratio, ADHD, bipolar disorder, major depressive disorder, neuroticism, and schizophrenia were all positively significantly correlated with tiredness. One interesting result of this investigation revealed that even when controlling for the presence of type 2 diabetes, the genetic link between tiredness and polygenic risk score for type 2 diabetes remained significant. This means that predisposition to type 2 diabetes and tiredness have an underlying genetic association regardless of the presence of morbidity, as reported by individuals. High-density lipoprotein cholesterol, forced expiratory volume in one second, grip strength, self-rated health, and verbal-numerical reasoning were found to be significantly negatively correlated with feelings of tiredness. Moreover, no significant sex differences between males and females were found. This study revealed the first estimation of how genetic variants contribute to the heritability of tiredness. An 8.4% significant single nucleotide polymorphism-based heritability was determined for tiredness. It is clear that a multitude of factors contribute to self-reported tiredness, including affective, cognitive, behavioral, and physical contributors. Fatigue is influenced by many genes and is therefore heterogeneous and multifactorial. Although many disparate genes seem to contribute to fatigue, a majority of these genes are associated with metabolic syndrome and are biomarkers for prolonged stress on the body (known as allostatic load). It is therefore possible that the genetic overlap between many of these factors and fatigue is due to the body’s physiological stress response. While this study is limited by self-reports of tiredness, a restrictive sample of middle- and older-aged adults of white British ancestry, and the possibility that tiredness is too complex and heterogeneous to meaningfully study on the genetic level, this study is the first to quantitate any genetic underpinning to fatigue. Genetic predispositions do exist for various mental and physical health complaints and may influence individuals to report a lack of energy. More data must be collected and more studies must be carried out, but it is clear that there is value in conducting future investigations because tiredness extends beyond our behavioral choices. While sleep, exercise, diet, social environment, and mental-health are just some of the important factors influencing energy and tiredness, there is much more to the picture. Next time you are feeling fatigued, it may not be so easy as to just get a few more hours of sleep since genetics seems to play a role as well. REFERENCES V Deary, SP Hagenaars, SE Harris, WD Hill, G Davies, DCM Liewald, International Consortium for Blood Pressure GWAS, CHARGE Consortium Aging and Longevity Group, CHARGE Consortium Inflammation Group, AM McIntosh, CR Gale and IJ Deary. Genetic contributions to self-reported tiredness. Molecular Psychiatry. February 2017. 00, 1-12.