Human Molecular Genetics

Human populations differ in disease prevalences and in average values of phenotypes, but the extent to which differences are caused by genetic or environmental factors is unknown for most complex traits. Comparing phenotypic means across populations is confounded by environmental differences and comparisons based on polygenic predictors can lead to biased inference1,2. Family-based analyses of genetically admixed individuals offer a powerful framework for disentangling the direct and associated ...

BackgroundThere are substantial differences in the clinical presentation of type 1 diabetes (T1D) depending on the first-developing autoantibody, although the underlying mechanisms are poorly understood. The DR3-DQ2 (DR3) and DR4-DQ8 (DR4) haplotypes at the MHC locus closely associate with GAD and IAA as the first-developing autoantibody, respectively, and can therefore be used as proxies for first autoantibody development in large cohort studies of T1D cases and controls. MethodsWe performed t...

BackgroundC-reactive protein (CRP) is a well-established biomarker of systemic inflammation. In pregnancy, several studies show association of elevated CRP with gestational diabetes mellitus (GDM). However, the genetic contributions of CRP levels during early pregnancy and their potential association with GDM remain largely understudied. MethodsWe conducted maternal and offspring genome-wide association studies (GWAS) of first-trimester CRP levels in the Nulliparous Pregnancy Outcomes Study: Mo...

BackgroundEpigenetic alterations during fetal development have been proposed as key factors explaining associations between maternal lifestyle during pregnancy and later health outcomes in the offspring, pertaining to the developmental origin of health and disease (DOHAD) hypothesis. ObjectivesTo assess the association of maternal lifestyle with offsprings birth weight and underlying epigenetic mediatory mechanisms in the NorthPop prospective birth cohort. MethodsA three-step analytic pipeline...

BackgroundMicroRNAs (miRNAs) are a class of small non-coding RNAs regulating gene expression. They are involved in many biological processes, including adaptation to pregnancy. The identification of genetic variants associated with gene expression, known as expression quantitative trait loci (eQTL), helps to understand the underlying molecular mechanisms and determinants of complex diseases. Using data from the prospective pre-birth Gen3G cohort, we investigated associations between maternal gen...

BackgroundBirthweight is heritable and strongly associated with epigenetic differences at birth. It is unclear whether a genetic birthweight score is associated with DNA methylation (DNAm) and, if so, whether through direct genetic effects (i.e., child genotype) or indirect genetic effects (i.e., parental genotype, independent of child genotype), which are suspected to be mediated by the prenatal environment (e.g. metabolic factors). MethodsWe constructed polygenic scores (PGS) for birthweight ...

Knee pain is a widespread musculoskeletal condition affecting millions globally, with significant socio-economic implications. This study endeavors to identify genetic variants associated with knee pain through a comprehensive genome-wide association study (GWAS) using data from 441,757 individuals in the UK Biobank. The primary GWAS identified ten significant loci, including eight novel loci, with the most significant single nucleotide polymorphism (SNP) being rs143384 near the GDF5 gene on chr...

BackgroundPolygenic risk scores (PRSs) improve type 2 diabetes (T2D) prediction beyond clinical risk factors but perform poorly in non-European populations, where T2D burden is often higher, undermining their global clinical utility. MethodsWe conducted the largest global effort to date to harmonize T2D genome-wide association study (GWAS) meta- analyses across five ancestries--European (EUR), African/African American (AFR), Admixed American (AMR), South Asian (SAS), and East Asian (EAS)--inclu...

Clinical observations have linked tobacco smoking with increased type 2 diabetes risk (1-5), a major public health concern (6). Mendelian randomization analysis has recently suggested smoking may be a causal risk factor for type 2 diabetes (7). However, this initial association could be mediated by additional causal risk factors correlated with smoking behavior, which have not been investigated to date. We hypothesized that body mass index (BMI) could explain the association between smoking and ...

BackgroundDNA methylation (DNAm) may play an important role in birth outcomes. Material and MethodsGenome wide DNAm was analysed in peripheral blood DNA of women at multiple time points during gestation. A novel empirical method was used to identify CpG sites with high temporal variance in methylation associating with preterm birth. ResultsHigh variability at 1296 CpG sites from the promoter regions of 1197 genes significantly associated with PTB. These genes belonged to pathways involved in s...

Gestational diabetes mellitus (GDM) affects [~]14% of pregnancies and is linked to adverse pregnancy outcomes and increased maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium conducted trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identified 37 GDM-associated loci (19 novel) and five novel loci for glycemic traits, all operating through the maternal genome. M...

BackgroundAccumulating evidence links paternal adiposity in the peri-conceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans. Methods and findingsIn the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of co-ordinated epigenome-wide association studies (EWAS) of paternal prenatal Body Mass Index (BMI) (with and without adjustment for maternal BMI...

Type 2 diabetes (T2D) is a disease for which both common genetic variants and environmental factors influence risk. A few genes have been identified in which very rare variants have large effects on risk and here we carry out a weighted burden analysis of rare variants in a sample of over 200,000 exome-sequenced participants in the UK Biobank project, of whom over 13,000 have T2D. Variant weights were allocated based on allele frequency and predicted effect, as informed by a previous analysis of...

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the present study, we conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c ...

Previous studies have uncovered genetic loci associated with celiac disease (CeD) within both the human leukocyte antigen (HLA) and non-HLA regions. However, half of the heritability remains unexplained. This study aimed to identify novel loci associated with CeD in a general adult population screened for the disease, mitigating the likely selection bias observed in previous case-control studies. The study utilized data from the fourth Trondelag Health Study (HUNT4) in Norway, where 52,358 adult...

ImportanceType 2 diabetes mellitus (T2DM) and elevated glucose levels have been inversely associated with aortic aneurysms. However, the causality of this relationship remains uncertain. Additionally, there is a lack of studies investigating the association between glycemic traits and imaging-based thoracic aortic phenotypes. ObjectiveWe investigated whether T2DM and glycemic measures (fasting glucose (FG), fasting insulin (FI), glycated hemoglobin (HbA1c), and 2-hour post-load glucose (2hPG)) ...

AimsTo follow up results from an earlier study using an extended sample of 470,000 exome-sequenced subjects to identify genes associated with type 2 diabetes (T2D) and to characterise the distribution of rare variants in these genes. Materials and methodsExome sequence data for 470,000 UK Biobank participants was analysed using a combined phenotype for T2D obtained from diagnostic and prescription data. Gene-wise weighted burden analysis of rare coding variants in the new cohort of 270,000 samp...

Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mappin...

Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) among individuals but in a heterogeneous manner. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our s...

Type 2 diabetes (T2D) disproportionately affects individuals of South Asian ancestry (SAS), yet they remain underrepresented in genetic studies. We performed an exome-wide association study in 54,698 SAS T2D case: controls and follow-up metabolic trait evaluation. We identified ancestry-specific genes and protein-coding variants, including a SAS-specific variant in the known monogenic diabetes gene HNF4A (rs150776703, Pro437Ser), which was associated with protection from T2D (OR = 0.48, p = 2.8x...