The ability to extract multigenerational family relationships from large-scale population cohorts provides a powerful means to understand the heritability of a wide range of diseases and their genetic relationships to each other. By showing how the heritability of broad diagnostic categories changes over time and how said categories are related on the genetic level, our analysis of the Danish genealogy and linked national patient registers illustrates the vast potential of this resource in current biomedical research.
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 9 was highest for gastrointestinal conditions (average rg = 0.567, 95% CI = [0.566, 0.567]) and lowest for urogenital conditions (average rg = 0.386, 95% CI = [0.385, 0.388]). Mental, pulmonary, gastrointestinal, and neurological conditions had similar genetic correlation profiles.
[Keywords: heritability, genetic correlation, human disease, register data, Denmark, population registry]
…Genetic Correlations: To understand the mutual relationships between the 10 broad diagnostic categories (15), we estimated their genetic correlations (rg) by combining within-category and between-category estimates of the latent correlation into Falconer’s method (16). We considered all family relations within a radius of 3 meioses and restricted the analyses to the 4 most data-rich demographic cohorts mentioned in Genealogy Network Structure (Figure 4 & Dataset S1).
All rg except 2 were positive, and all of them except one were also statistically-significantly different from zero. Overall, rg were highly consistent between consecutive cohorts, thus further boosting confidence in the estimates (SI Appendix, Figure 7). This trend was more marked for certain diagnostic categories such as mental, pulmonary, and neurological than others. In all 10 diagnostic categories, younger cohorts showed lower rg than older generations, whereas the opposite trend was observed for heritability that consistently increased in younger cohorts (Figure 4 & SI Appendix, Dataset S1). The average rg of each of the 10 diagnostic categories with the other 9 categories was highest for gastrointestinal conditions (0.567; SE = 0.0005) and lowest for urogenital conditions (0.386; SE = 0.0008).
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