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The single-step genomic model has become the golden standard for routine evaluation in livestock species, such as Holstein dairy cattle. The single-step genomic model with direct estimation of marker effects has been proven to be efficient in accurately accounting for millions of genotype records. For diverse applications including frequent genomic evaluation updates on a weekly basis, estimates of the marker effects from the single-step evaluations play a central role in genomic prediction. In this study we focused on exploring the marker effect estimates from the single-step evaluation. Phenotypic, genotypic, and pedigree data were taken from the official evaluation for German dairy breeds in April 2021. A multilactation random regression test-day model was applied to more than 242 million test-day records separately for 4 traits: milk, fat, and protein yields, and somatic cell scores (SCS). Approximately one million genotyped Holstein animals were considered in the single-step genomic evaluations including ∼21 million animals in pedigree. Deregressed multiple across-country breeding values of Holstein bulls having daughters outside Germany were integrated into the national test-day data to increase the reliability of genomic breeding values. To assess the stability and bias of the marker effects of the single-step model, test-day records of the last 4 yr were deleted, and the integrated bulls born in the last 4 yr were truncated from the complete phenotypic dataset. Estimates of the marker effects were shown to be highly correlated, with correlations ∼0.9, between the full and truncated evaluations. Regression slope values of the marker-effect estimates from the full on the truncated evaluations were all close to their expected value, being ∼1.03. Calculated using random regression coefficients of the marker effect estimates, drastically different shapes of the genetic lactation curve were seen for 2 markers on chromosome 14 for the 4 test-day traits. The contribution of individual chromosomes to the total additive genetic variances seemed to follow the polygenic inheritance mode for protein yield and SCS. However, chromosome 14 was found to make an exceptionally large contribution to the total additive genetic variance for milk and fat yields because of markers near the major gene DGAT1. For the first lactation test-day traits, we obtained ∼0 correlations of chromosomal direct genomic values between any pair of the chromosomes; no spurious correlations were found in our analysis, thanks to the large reference population. For trait milk yield, chromosomal direct genomic values appeared to have a large variation in the between-lactation correlations among the chromosomes, especially between first and second or third lactations. The optimal features of the random regression test-day model and the single-step marker model allowed us to track the differences in the shapes of genetic lactation curves down to the individual markers. Furthermore, the single-step random regression test-day model enabled us to better understand the inheritance mode of the yield traits and SCS (e.g., variable chromosomal contributions to the total additive genetic variance and to the genetic correlations between lactations). [ABSTRACT FROM AUTHOR]

The outbreak of Covid-19 negatively affected mental health and increased loneliness. The subjective feeling of loneliness is influenced by genetic and social factors and has a negative impact on mental health. From March 2020 to June 2021 loneliness was investigated in N = 517 individuals using monthly acquired questionnaire data and Latent Growth Curve Analysis. Associations of social factors and polygenic risk scores (PRSs, n = 361) with class membership were investigated. Three classes ("average", 40%; "not lonely", 38%; "elevated loneliness", 22%) were identified, that differ significantly regarding loneliness, mental dysfunction, and response to the lockdown phases. Individuals with a high PRS for neuroticism are more likely to belong to the "elevated loneliness" class, living with another person is a protective factor. As the "elevated loneliness" class was at the highest risk of mental dysfunction, our findings underscore the importance of identifying those individuals to implement counteractive measures. [ABSTRACT FROM AUTHOR]

Background: In order to utilize polygenic risk scores (PRSs) for Alzheimer's disease (AD) in a meaningful way, influential factors (i.e. training set) and prediction across groups such as APOE e4 (APOE4) genotype as well as associations to dementia-related biomarkers should be explored. Therefore, we examined the association of APOE4 and various PRSs, based on training sets that utilized differing AD definitions, with incident AD and all-cause dementia (ACD) within 17 years, and with levels of phosphorylated tau181 (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) in blood. Secondarily, effect modification by APOE4 status and sex was examined. Methods: In this prospective, population-based cohort study and nested case–control study, 9,940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed for up to 17 years. Participants were included in this study if dementia status and genetic data were available. A subsample of participants additionally had measurements of P-tau181, NfL, and GFAP obtained from blood samples. Cox and logistic regression analyses were used to assess the association of genetic risk (APOE genotype and PRSnoAPOE) with incident ACD/AD and log-transformed blood levels of P-tau181, NfL, and GFAP. Results: Five thousand seven hundred sixty-five participants (54% female, aged 50-75years at baseline) were included in this study, of whom 464 received an all-cause dementia diagnosis within 17 years. The PRSs were not more predictive of dementia than APOE4. An APOE4 specific relationship was apparent with PRSs only exhibiting associations to dementia among APOE4 carriers. In the nested case–control study including biomarkers (n = 712), APOE4 status and polygenic risk were significantly associated to levels of GFAP in blood. Conclusions: The use of PRSs may be beneficial for increased precision in risk estimates among APOE4 carriers. While APOE4 may play a crucial etiological role in initial disease processes such as Aβ deposition, the PRS may be an indicator of further disease drivers as well as astrocyte activation. Further research is necessary to confirm these findings, especially the association to GFAP. [ABSTRACT FROM AUTHOR]

The availability of polygenic scores for type 2 diabetes (T2D) raises the question, whether assessing family history might become redundant. However, family history not only involves shared genetics, but also shared environment. It was the aim of this study to assess the independent and combined effects of one family risk score (FamRS) and a polygenic score (PGS) on prevalent and incident T2D risk in a population-based study from Germany (n = 3071). The study was conducted in 2004/2005 with up to 12 years of follow-up. The FamRS takes into account not only the number of diseased first grade relatives, but also age at onset of the relatives and age of participants. 256 prevalent and additional 163 incident T2D cases were recorded. Prevalence of T2D increased sharply for those within the top quantile of the PGS distribution resulting in an OR of 19.16 (p < 2 × 10–16) for the top 20% compared to the remainder of the population, independent of age, sex, BMI, physical activity and FamRS. On the other hand, having a very strong family risk compared to average was still associated with an OR of 2.78 (p = 0.001), independent of the aforementioned factors and the PGS. The PGS and FamRS were only slightly correlated (r2Spearman = 0.018). The combined contribution of both factors varied with varying age-groups, though, with decreasing influence of the PGS with increasing age. To conclude, both, genetic information and family history are relevant for the prediction of T2D risk and might be used for identification of high risk groups to personalize prevention measures. [ABSTRACT FROM AUTHOR]

• Host genetic factors impact susceptibility to and severity of COVID-19 • The 3p31.21 locus replicates as a risk factor for severe COVID-19 • The CCL2 polymorphism rs1024611 is associated with susceptibility to infection • A polygenic risk score can predict hospitalization in patients with COVID-19 Host genetic factors contribute to the variable severity of COVID-19. We examined genetic variants from genome-wide association studies and candidate gene association studies in a cohort of patients with COVID-19 and investigated the role of early SARS-CoV-2 strains in COVID-19 severity. This case-control study included 123 COVID-19 cases (hospitalized or ambulatory) and healthy controls from the state of Baden-Wuerttemberg, Germany. We genotyped 30 single nucleotide polymorphisms, using a custom-designed panel. Cases were also compared with the 1000 genomes project. Polygenic risk scores were constructed. SARS-CoV-2 genomes from 26 patients with COVID-19 were sequenced and compared between ambulatory and hospitalized cases, and phylogeny was reconstructed. Eight variants reached nominal significance and two were significantly associated with at least one of the phenotypes "susceptibility to infection", "hospitalization", or "severity": rs73064425 in LZTFL1 (hospitalization and severity, P <0.001) and rs1024611 near CCL2 (susceptibility, including 1000 genomes project, P = 0.001). The polygenic risk score could predict hospitalization. Most (23/26, 89%) of the SARS-CoV-2 genomes were classified as B.1 lineage. No associations of SARS-CoV-2 mutations or lineages with severity were observed. These host genetic markers provide insights into pathogenesis and enable risk classification. Variants which reached nominal significance should be included in larger studies. [ABSTRACT FROM AUTHOR]

Genetic risk scores for common diseases as myocardial infarction (MI) gain increasing attention for individual's risk prediction. One might wonder if assessing family history becomes redundant. It was the aim of this study to evaluate the amount of shared information between family history and genetic risk scores and to assess their independent and combined effects on prevalent and incident MI risk. A genome wide polygenic risk score (PGS) and one family risk score (FamRS) were calculated in a population-based study from Southern Germany (n = 3071) with up to 11 years of follow-up. Logistic and Cox Regression models were used adjusting for lifestyle and classical risk factors. A right shift in MI risk for increasing values of PGS was found, with. considerably increasing ORs along the top quantiles of PGS (OR = 3.03 for top 10%; OR = 5.55 for top 2.5%). The PGS was not associated with incident MI cases, though. The FamRS was significantly associated with both prevalent and incident MI cases with an OR of 2.9 for participants with a strong positive family history compared to average. ORs and HRs did hardly change in a combined model including both measures, indicating independent contribution to MI risk. The simultaneous addition of PGS and FamRS to a model including classical risk factors significantly enhanced prediction for prevalent cases and non-cases (p = 3.28 × 10−5). These findings emphasize that both genetic information and family history are relevant for the determination of MI risk and that neither of them can replace the other. [Display omitted] • A genome-wide polygenic risk score (PGS) was shown to be a strong risk predictor for especially "early" prevalent myocardial infarction (MI) cases. • A family risk score (FamRS) was a stronger predictor than simpler family history measures as "diseased parents". • The FamRS was highly informative for both prevalence and incidence. • Addition of PGS and FamRS to a model including classical risk factors enhanced prediction for prevalent cases and non-cases. [ABSTRACT FROM AUTHOR]

Background: Rigorous evaluation of the calibration and discrimination of breast-cancer risk-prediction models in prospective cohorts is critical for applications under clinical guidelines. We comprehensively evaluated an integrated model incorporating classical risk factors and a 313-variant polygenic risk score (PRS) to predict breast-cancer risk.Methods: Fifteen prospective cohorts from six countries with 239 340 women (7646 incident breast-cancer cases) of European ancestry aged 19-75 years were included. Calibration of 5-year risk was assessed by comparing expected and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future cases crossing clinically relevant risk thresholds.Results: Among women <50 years old, the median (range) expected-to-observed ratio for the integrated model across 15 cohorts was 0.9 (0.7-1.0) overall and 0.9 (0.7-1.4) at the highest-risk decile; among women ≥50 years old, these were 1.0 (0.7-1.3) and 1.2 (0.7-1.6), respectively. The proportion of women identified above a 3% 5-year risk threshold (used for recommending risk-reducing medications in the USA) ranged from 7.0% in Germany (∼841 000 of 12 million) to 17.7% in the USA (∼5.3 of 30 million). At this threshold, 14.7% of US women were reclassified by adding the PRS to classical risk factors, with identification of 12.2% of additional future cases.Conclusion: Integrating a 313-variant PRS with classical risk factors can improve the identification of European-ancestry women at elevated risk who could benefit from targeted risk-reducing strategies under current clinical guidelines. [ABSTRACT FROM AUTHOR]