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Family history is the standard indirect measure of inherited susceptibility in clinical care, whereas polygenic risk scores (PRSs) have more recently demonstrated potential for more directly capturing genetic risk in many diseases. Few studies have systematically compared how these overlap and complement each other across common diseases. Within FinnGen (N = 306,418), we leverage family relationships, up to 50 years of nationwide registries, and genome-wide genotyping to examine the interplay of family history and genome-wide PRSs. We explore the dynamic for three types of family history across 24 common diseases: first- and second-degree family history and parental causes of death. Covering a large proportion of the burden of non-communicable diseases in adults, we show that family history and PRS are independent and not interchangeable measures, but instead provide complementary information on inherited disease susceptibility. The PRSs explained on average 10% of the effect of first-degree family history, and first-degree family history 3% of PRSs, and PRS effects were independent of both early- and late-onset family history. The PRS stratified the risk similarly in individuals with and without family history. In most diseases, including coronary artery disease, glaucoma, and type 2 diabetes, a positive family history with a high PRS was associated with a considerably elevated risk, whereas a low PRS compensated completely for the risk implied by positive family history. This study provides a catalogue of risk estimates for both family history of disease and PRSs and highlights opportunities for a more comprehensive way of assessing inherited disease risk across common diseases. [Display omitted] Leveraging family relationships, nationwide registries, and genome-wide genotyping, Mars et al. systematically compared two measures of inherited disease risk across 24 diseases: family history and polygenic risk scores. The measures provided complementary information for risk assessment, demonstrating opportunities for a more comprehensive way of assessing inherited risk in clinical care. [ABSTRACT FROM AUTHOR]

Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease. [ABSTRACT FROM AUTHOR]

Spontaneous dizygotic (DZ) twinning occurs in 1%–4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB , p = 1.54 × 10 −9 , and rs17293443 in SMAD3 , p = 1.57 × 10 −8 ) and replicated (p = 3 × 10 −3 and p = 1.44 × 10 −4 , respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3 , the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health. [ABSTRACT FROM AUTHOR]