Type 1 diabetes genetic risk contributes to phenotypic presentation in monogenic autoimmune diabetes.

Disease-causing variants in key immune homeostasis genes can lead to monogenic autoimmune diabetes. Some individuals carrying disease-causing variants do not develop autoimmune diabetes, even though they develop other autoimmune disease. We aimed to determine whether type 1 diabetes polygenic risk contributes to phenotypic presentation in monogenic autoimmune diabetes.

Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance.

Background: Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight.

Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.

Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.

Identification and analysis of individuals who deviate from their genetically-predicted phenotype.

Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes.

The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus.

ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and β-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in two subjects, and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank.

Utility of genetic risk scores in type 1 diabetes.

Iterative advances in understanding of the genetics of type 1 diabetes have identified >70 genetic regions associated with risk of the disease, including strong associations across the HLA class II region that account for >50% of heritability. The increased availability of genetic data combined with the decreased costs of generating these data, have facilitated the development of polygenic scores that aggregate risk variants from associated loci into a single number: either a genetic risk score (GRS) or a polygenic risk score (PRS). PRSs incorporate the risk of many possibly correlated variants from across the genome, even if they do not reach genome-wide significance, whereas GRSs estimate the cumulative contribution of a smaller subset of genetic variants that reach genome-wide significance.

Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.

Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion, after accounting for BMI in adulthood.

Aims/hypothesis: Determining how high BMI at different time points influences the risk of developing type 2 diabetes and affects insulin secretion and insulin sensitivity is critical.

Methods: By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from those of high adulthood BMI on the risk of type 2 diabetes and insulin-related phenotypes using Mendelian randomisation.

Identification and analysis of individuals who deviate from their genetically-predicted phenotype.

Unlabelled: Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes.

Recurrent 17q12 microduplications contribute to renal disease but not diabetes.

Background: 17q12 microdeletion and microduplication syndromes present as overlapping, multisystem disorders. We assessed the disease phenotypes of individuals with 17q12 CNV in a population-based cohort.

Methods: We investigated 17q12 CNV using microarray data from 450 993 individuals in the UK Biobank and calculated disease status associations for diabetes, liver and renal function, neurological and psychiatric traits.