Quantifying the relative importance of genetics and environment on the comorbidity between mental and cardiometabolic disorders using 17 million Scandinavians

Abstract

Mental disorders are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders. Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and near-complete genealogies of Denmark and Sweden (n = 17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six mental disorders and 15 cardiometabolic disorders. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with cardiometabolic disorders, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with cardiometabolic disorders was mainly or fully driven by environmental factors. In this work we provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.

Fig. 1. Cumulative incidences and 95% confidence intervals of ADHD for individuals born 1981–2005 using medical records up to 2012 stratified by year of birth.

Cumulative incidences are shown for (A) the general population (n = 1,560,901 individuals), (B) individuals with at least one full-sibling diagnosed with ADHD (n = 24,476 individuals), (C) individuals with at least one parent diagnosed with type-2 diabetes (n = 5557 individuals). Confidence intervals are reported as cumulative incidence estimates at a given age for a specific year of birth +/− 1.96 × standard error.

Fig. 2. Meta-analysis of Danish and Swedish narrow sense heritability (h²) estimates and 95% confidence intervals of mental- and cardiometabolic disorders.

Estimates were calculated using information from all individuals born in Denmark (n = 7,797,720) and Sweden (n = 13,222,453). ADHD attention deficit/hyperactivity disorder, ICA intracranial aneurysm, CIHD chronic ischaemic heart disease. Confidence intervals are reported as the meta-analysis of Danish and Swedish narrow sense h² estimates +/− 1.96 × standard error.

Fig. 3. Meta-analysis of Danish (n = 1,560,901) and Swedish (n = 2,566,100) genetic correlations (r_g) estimates between mental- and cardiometabolic disorders and 95% confidence intervals calculated using national register data.

Individuals were born between 1981 and 2005 using medical records up to 2012. ADHD attention-deficit/hyperactivity disorder, ICA intracranial aneurysm, CIHD chronic ischaemic heart disease. Confidence intervals are reported as the meta-analysis of Danish and Swedish r_g estimates +/− 1.96 × standard error.

Fig. 4. Quantification of the contribution of genetic (G) and the non-genetic (E) factors to the observed phenotypic correlation (r_p) between mental- and cardiometabolic disorders using register based genetic correlations (r_g) and heritability (h²) estimates.

Estimates of r_p were selected from Momen et al. . Individuals were born between 1981 and 2005 using medical records up to 2012 (n = 1,560,901). Confidence intervals are reported as either (a) phenotypic correlation estimate +/− 1.96 × standard error, (b) non-genetic (E) component +/− 1.96 × standard error, or (c) genetic (F) component +/− 1.96 × standard error.