In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

19Genotype imputation has become a standard technique prior genome-wide association studies 20 (GWASs). For common and low-frequency variants, genotype imputation can be performed 21 sufficiently accurately with publicly available and ethnically heterogeneous imputation reference 22 panels like 1000 Genomes Project (1000G) and Haplotype Reference Consortium. However, the 23 imputation of rare variants has been shown to be significantly more accurate when ethnically matched 24 reference panel is used. Even more, greater genetic similarity between reference panel and target 25 samples facilitates the detection of rare (or even population-specific) causal variants. Notwithstanding, 26 the genome-wide downstream consequences and differences of using ethnically mixed and matched 27 reference panels have not been yet comprehensively explored. 28We determined and quantified these differences by performing several comparative evaluations of the 29 discovery-driven analysis scenarios. A variant-wise GWAS was performed on seven complex diseases 30 and body mass index by using genome-wide genotype data of ~37,000 Estonians imputed with 31 ethnically mixed 1000G and ethnically matched imputation reference panels. Although several 32 previously reported common (minor allele frequency; MAF > 5%) variant associations were replicated 33 in both imputed datasets, no major differences were observed among the genome-wide significant 34 findings or in the fine-mapping effort. In the analysis of rare (MAF < 1%) coding variants, 46 35 significantly associated genes were identified in the ethnically matched imputed data as compared to 36 four genes in the 1000G panel based imputed data. All resulting genes were consequently studied in 37 the UK Biobank data. 38These associated genes provide an example of how rare variants can be efficiently analysed to 39 discover novel, potentially functional genetic variants in relevant phenotypes. Furthermore, our work 40 serves as proof of a cost-efficient study design, demonstrating that the usage of ethnically matched 41 imputation reference panels can enable improved imputation of rare variants, facilitating novel high-42confidence findings in rare variant GWAS scans. 43 3 Author summary 44 Over the last decade, genome-wide association studies (GWASs) have been widely used for detecting 45 genetic biomarkers in a wide range of traits. Typically, GWASs are carried out using chip-based 46 genotyping data, which are then combined with a more densely genotyped reference panel to infer 47 untyped genetic variants in chip-typed individuals. The latter method is called imputation and its 48 accuracy depends on multiple factors. Publicly available and ethnically heterogeneous imputation 49 reference panels (IRPs) such as 1000 Genomes Project (1000G) are sufficiently accurate for imputation 50 of common and low-frequency variants, but custom ethnically matched IRPs outperform these in case 51 of rare variants. In this work, we systematically compare downstream association analysis effects on 52 eight com...

Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers and offered return of results with genetic counseling. We evaluated participants responses to and the clinical utility of the reporting of actionable genetic findings. Twenty-two of 40 contacted carriers of 17 pathogenic BRCA1/2 variants responded and chose to receive results. Eight of these 22 participants qualified for high-risk assessment based on National Comprehensive Cancer Network criteria. Twenty of 21 counseled participants appreciated being contacted. Relatives of 10 participants underwent cascade screening. Five of 16 eligible female BRCA1/2 variant carriers chose to undergo risk-reducing surgery, and 10 adhered to surveillance recommendations over the 30-month follow-up period. We recommend the return of results to population-based biobank participants; this approach could be viewed as a model for population-wide genetic testing. The genotype-first approach permits the identification of individuals at high risk who would not be identified by application of an approach based on personal and family histories only.