The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra.

De novo germline mutation is an important factor in the evolution of allelic diversity and disease predisposition in a population. Here, we study the influence of genetically-inferred ancestry and environmental factors on de novo mutation rates and spectra. Using a genetically diverse sample of ~10 K whole-genome sequenced trios, one of the largest de novo mutation catalogues to date, we found that genetically-inferred ancestry is associated with modest but significant changes in both germline mutation rate and spectra across continental populations.

Widespread recessive effects on common diseases in a cohort of 44,000 British Pakistanis and Bangladeshis with high autozygosity.

Genetic association studies have focused on testing additive models in cohorts with European ancestry. Little is known about recessive effects on common diseases, specifically for non-European ancestry. Genes & Health is a cohort of British Pakistani and Bangladeshi individuals with elevated rates of consanguinity and endogamy, making it suitable to study recessive effects.

Exome sequencing of UK birth cohorts.

Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights ranging from population genetics to applications across the social sciences.

Investigating misclassification of type 1 diabetes in a population-based cohort of British Pakistanis and Bangladeshis using polygenic risk scores.

Correct classification of type 1 (T1D) and type 2 diabetes (T2D) is challenging due to overlapping clinical features and the increasingly early onset of T2D, particularly in South Asians. Polygenic risk scores (PRSs) for T1D and T2D have been shown to work relatively well in South Asians, despite being derived from largely European-ancestry samples. Here we used PRSs to investigate the rate of potential misclassification of diabetes amongst British Bangladeshis and Pakistanis.

Examining the role of common variants in rare neurodevelopmental conditions.

Although rare neurodevelopmental conditions have a large Mendelian component, common genetic variants also contribute to risk. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family environment also play a role.

Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases.

Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture for 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.

Influence of autozygosity on common disease risk across the phenotypic spectrum.

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (F) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of F.

Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases.

Polygenic risk scores (PRS) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. Validation and transferability of existing PRS across independent datasets and diverse ancestries are limited, which hinders the practical utility and exacerbates health disparities. We propose PRSmix, a framework that evaluates and leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture.

Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistani and Bangladeshi individuals.

Individuals with South Asian ancestry have a higher risk of heart disease than other groups but have been largely excluded from genetic research. Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort, we conducted genome-wide association studies of coronary artery disease and its key risk factors. Using power-adjusted transferability ratios, we found evidence for transferability for the majority of cardiometabolic loci powered to replicate.

Integrating polygenic risk scores in the prediction of type 2 diabetes risk and subtypes in British Pakistanis and Bangladeshis: A population-based cohort study.

Background: Type 2 diabetes (T2D) is highly prevalent in British South Asians, yet they are underrepresented in research. Genes & Health (G&H) is a large, population study of British Pakistanis and Bangladeshis (BPB) comprising genomic and routine health data. We assessed the extent to which genetic risk for T2D is shared between BPB and European populations (EUR).

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro.

Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk.

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4 T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively.

Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria.

By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of (expected ~1 in 30 million outbred people). (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67).

Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy.

Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines.

Power, false discovery rate and Winner's Curse in eQTL studies.

Investigation of the genetic architecture of gene expression traits has aided interpretation of disease and trait-associated genetic variants; however, key aspects of expression quantitative trait loci (eQTL) study design and analysis remain understudied. We used extensive, empirically driven simulations to explore eQTL study design and the performance of various analysis strategies. Across multiple testing correction methods, false discoveries of genes with eQTLs (eGenes) were substantially inflated when false discovery rate (FDR) control was applied to all tests and only appropriately controlled using hierarchical procedures.

2-[(4,6-Dimeth-oxy-pyrimidin-2-yl)-oxy]benzaldehyde.

In the title compound, C(13)H(12)N(2)O(4), the dihedral angle between the benzene and pyrimidine rings is 55.57 (13)°. The carbonyl group and the two methoxyl groups are approximately coplanar with the benzene ring and pyrimidine ring; the C-C-C-O, C-O-C-N and C-O-C-C torsion angles being -6.