A comprehensive map of genetic relationships among diagnostic categories based on 48.6 million relative pairs from the Danish genealogy

For more than half a century, Denmark has maintained population-wide demographic, health care, and socioeconomic registers that provide detailed information on the interaction between all residents and the extensive national social services system. We leverage this resource to reconstruct the genealogy of the entire nation based on all individuals legally residing in Denmark since 1968. We cross-reference 6,691,426 individuals with nationwide health care registers to estimate heritability and genetic correlations of 10 broad diagnostic categories involving all major organs and systems. Heritability estimates for mental disorders were consistently the highest across demographic cohorts (average h² = 0.406, 95% CI = 0.403, 0.408]), whereas estimates for cancers were the lowest (average h² = 0.130, 95% CI = 0.125, 0.134]). The average genetic correlation of each of the 10 diagnostic categories with the other nine was highest for gastrointestinal conditions (average r_g = 0.567, 95% CI = 0.566, 0.567]) and lowest for urogenital conditions (average r_g = 0.386, 95% CI = 0.385, 0.388]). Mental, pulmonary, gastrointestinal, and neurological conditions had similar genetic correlation profiles.

Denmark, like other Nordic countries (1–4), has maintained for more than half a century population-wide demographic, health care, and socioeconomic registers that provide detailed information on the interaction between all residents and the extensive national social services system (5, 6), including familial information via parental links (7, 8). This has allowed population-based studies of the causes and consequences of disease at an unprecedented scale and detail (9).Several studies in the Nordic countries have leveraged diagnostic information from cross-referenced civil and health care registers on pairs of close relatives for quantitative genetic studies—that is, co-occurrence and familial coaggregation, heritability and genetic correlation, and nonrandom mating (10–14). However, the dynamics of a population (e.g., changes in mating patterns and family structure, health care provision, clinical practice, and diagnostic systems) may compromise such initiatives and bias quantitative genetic estimates and inference on human behavior. Thus, realizing the potential of Nordic population and health care registers depends on insights into the structure and network properties of the entire genealogy and accounting for underlying changes in the frequencies of human traits, notably in population demographics and disease frequencies.Here, we reconstruct the Danish genealogy using the population-wide Danish Civil Registration System that holds information on family relationships for all individuals with at least 1 d of legal residence in Denmark since 1968 (7, 8). We describe the size, structure, and network properties of the genealogy along 116 y. We leverage the cross-reference to the nationwide, public, and health care registers to estimate occurrence, heritability, and genetic correlations for 10 broad categories of medical conditions across eight consecutive demographic cohorts.