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 (h(2)) and genetic correlations (r(G)). All analyses were adjusted for age, age(2), 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 h(2)(depression) = 0.25 to h(2)(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.