Familial co-aggregation and shared heritability between depression, anxiety, obesity and substance use

Depression, anxiety, obesity and substance use are heritable and often co-occur. However, the mechanisms underlying this co-occurrence are not fully understood. We estimated their familial aggregation and co-aggregation as well as heritabilities and genetic correlations to improve etiological understanding. Data came from the multi-generational population-based Lifelines Cohort Study (n = 162,439). Current depression and anxiety were determined using the MINI International Neuropsychiatric Interview. Smoking, alcohol and drug use were assessed by self-report questionnaires. Body mass index (BMI) and obesity were calculated by measured height and weight. Modified Cox proportional hazards models estimated recurrence risk ratios (λ_R), and restricted maximum likelihood variance decomposition methods estimated heritabilities (h²) and genetic correlations (r_G). All analyses were adjusted for age, age², and sex. Depression, anxiety, obesity and substance use aggregated within families (λ_{R first-degree relative} = 1.08-2.74) as well as between spouses (λ_R = 1.11-6.60). All phenotypes were moderately heritable (from h²_depression = 0.25 to h²_BMI = 0.53). Depression, anxiety, obesity and smoking showed positive familial co-aggregation. That is, each of these traits confers increased risk on the other ones within families, consistent with the positive genetic correlations between these phenotypes (r_G = 0.16-0.94). The exception was obesity, which showed a negative co-aggregation with alcohol and drug use and vice versa, consistent with the negative genetic correlations of BMI with alcohol (r_G = -0.14) and soft drug use (r_G = -0.10). Patterns of cross-phenotype recurrence risk highlight the co-occurrence among depression, anxiety, obesity and substance use within families. Patterns of genetic overlap between these phenotypes provide clues to uncovering the mechanisms underlying familial co-aggregation.