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Using Scandinavian pedigrees to disentangle mechanisms of shared familial risk in psychiatric and cardiometabolic disorders

Using scandinavian genealogies to disentangle mechanisms of shared familial risk of psychiatric and cardiometabolic disorders

Nationwide Scandinavian pedigrees enable robust cross-country investigation of the co-occurrence of mental and cardiometabolic disorders, while also demonstrating that pedigree structure can shape register-based genetic inference.

The study aimed to investigate the familial aggregation and shared etiology of mental and cardiometabolic disorders by linking national pedigrees to health registers, and to systematically assess how pedigree structure affects these estimates across Scandinavia. Population-wide pedigrees were reconstructed from parent–child links in Denmark, Sweden, and Norway and linked to national patient registers; pedigree structure was compared in terms of connectivity, generational depth, number of relatives, and distribution of relationship types. Harmonized ICD-8 through ICD-10 definitions covered major depressive disorder, autism spectrum disorder, bipolar disorder, schizophrenia, myocardial infarction, stroke, type 2 diabetes, and composite cardiovascular and cardiometabolic disorders; familial risks, register-based heritability, shared environmental effects, and genetic correlations were estimated, and country-specific estimates were pooled using random-effects meta-analysis. The pedigrees included approximately 6.8 million individuals in Denmark, 12.2 million in Sweden, and 7.8 million in Norway, comprising approximately 48, 114, and 66 million pairs of relatives, respectively, and spanning 6 to 7 generations. Pedigree structure differed across countries in connectivity, generational depth, and the distribution of relationship types; familial aggregation was strongest for neurodevelopmental disorders. Heritability ranged from 25% to 75%; the strongest genetic correlations were between major depressive disorder and stroke (0.21) and between major depressive disorder and type 2 diabetes (0.18). Cross-country differences were small to moderate and remained similar after relationship types were harmonized.

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