Genetic links between ovarian ageing, cancer risk and de novo mutation rates.

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing1. Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility1, with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan-that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk.

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.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.

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. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol (LDL-C). We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL-C and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions.

Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population.

Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from ∼200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population.

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.

The impact of Mendelian sleep and circadian genetic variants in a population setting.

Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants in these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts. We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data. We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. No carriers for variants reported in NPSR1 or PER2 were identified. We found no association between variants analyzed and extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being "definitely a morning person", P = 4x10-8; and had a 57-minute earlier midpoint sleep, P = 5x10-7). Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population.

Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study.

AIMS/HYPOTHESIS: Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. METHODS: Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0-29.0], HbA1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. RESULTS: Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (ß -1.53; 95% CI -2.76, -0.29). CONCLUSIONS/INTERPRETATION: Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function.

Diabetes Study of Children of Diverse Ethnicity and Race: Study design.

AIMS: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. MATERIALS AND METHODS: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non-fasting serum C-peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. RESULTS: The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. CONCLUSIONS: Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.

A founder UMOD variant is a common cause of hereditary nephropathy in the British population.

BACKGROUND: Monogenic disorders are estimated to account for 10%-12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin (UMOD) variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant. METHODS: Probands from 12 apparently unrelated pedigrees with a family history of kidney failure within a geographically contiguous UK region were shown to be heterozygous for a pathogenic variant of UMOD c.278_289delTCTGCCCCGAAG insCCGCCTCCT. RESULTS: A total of 88 clinically affected individuals were identified, all born in the UK and of white British ethnicity. 20 other individuals with the variant were identified in the UK 100,000 Genomes (100K) Project and 9 from UK Biobank (UKBB). A common extended haplotype was present in 5 of the UKBB individuals who underwent genome sequencing which was only present in <1 in 5000 of UKBB controls. Significantly, rare variants (<1 in 250 general population) identified within 1 Mb of the UMOD variant by genome sequencing were detected in all of the 100K individuals, indicative of an extended shared haplotype. CONCLUSION: Our data confirm a likely founder UMOD variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry.