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BackgroundHigher urate levels associate with higher systolic blood pressure (SBP) in adults, and in pregnancy, with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birth weight. We therefore tested for a causal effect of maternal urate on offspring birthweight.MethodsWe tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in UK Biobank (UKB; n=133,187) and Exeter Family Study of Childhood Health (EFSOCH; n=872). We conducted two-sample MR to test for a causal effect of maternal urate (114 single nucleotide polymorphisms [SNPs]; n=288,649 European-ancestry) on offspring birthweight (n=406,063 European-ancestry; maternal SNP effect estimates adjusted for fetal effects). Using one-sample MR (n=199,768 UKB women), we also tested for a causal relationship between urate and SBP.ResultsHigher maternal urate was associated with lower offspring birthweight in UKB (28g lower birthweight per 1-SD higher urate [95% CI: -31, -25]; P=1.8×10−75), with a similar effect estimate in EFSOCH (22g [95%CI: -50, 6]; P=0.13). The MR causal effect estimate was directionally consistent, but smaller (−11g [95% CI: -25, 3]; PIVW=0.13). In women, higher urate was causally associated with higher SBP (1.7 mmHg higher SBP per 1-SD higher urate [95% CI: 1.4, 2.1]; P=7.8×10−22) consistent with that previously published in women and men.ConclusionsThe marked attenuation of the MR result of maternal urate on offspring birthweight, compared to the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible weak effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.Key MessagesPrevious research suggests higher maternal serum urate in pregnancy is associated with lower offspring birthweight, and Mendelian randomization studies suggest a causal relationship between urate and systolic blood pressure (SBP), and SBP and birthweight; a causal effect of urate on birthweight has not yet been estimated, and thus it is also unknown whether it confounds maternal SBP-birthweight effects.The causal effect estimate of urate on offspring birthweight was directionally consistent, but weaker than, observational estimates; the estimate had 95% confidence intervals which included the null.This study confirmed a causal association between serum urate and higher SBP in women consistent with that published from a sample of both women and men.Maternal urate is unlikely to be a major determinant of birthweight or an important confounder of the causal relationship between SBP and lower birthweight.

Background17q12 microdeletion and microduplication syndromes present as overlapping, multisystem disorders. We assessed the disease phenotypes of individuals with 17q12 CNV in a population-based cohort.MethodsWe 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.ResultsWe identified 11 17q12 microdeletions and 106 microduplications. Microdeletions were strongly associated with diabetes (p=2×10−7) but microduplications were not. Estimated glomerular filtration rate (eGFR mL/min/1.73 m2) was consistently lower in individuals with microdeletions (p=3×10−12) and microduplications (p=6×10−25). Similarly, eGFR −9, p−9, p=0.009), respectively, highlighting sometimes substantially reduced renal function in each. Microduplications were associated with decreased fluid intelligence (p=3×10−4). SNP association analysis in the 17q12 region implicated changes toHNF1Bas causing decreased eGFR (NC_000017.11:g.37741642T>G, rs12601991, p=4×10−21) and diabetes (NC_000017.11:g.37741165C>T, rs7501939, p=6×10−17). A second locus within the region was also associated with fluid intelligence (NC_000017.11:g.36593168T>C, rs1005552, p=6×10−9) and decreased eGFR (NC_000017.11:g.36558947T>C, rs12150665, p=4×10–15).ConclusionWe demonstrate 17q12 microdeletions but not microduplications are associated with diabetes in a population-based cohort, likely caused byHNF1Bhaploinsufficiency. We show that both 17q12 microdeletions and microduplications are associated with renal disease, and multiple genes within the region likely contribute to renal and neurocognitive phenotypes.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

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. We performed two-sample MR using external studies of type 2 diabetes, and oral and intravenous measures of insulin secretion and sensitivity. Results We found that a childhood BMI that was one standard deviation (1.97 kg/m2) higher than the mean, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including increased insulin sensitivity index (β=0.15; 95% CI 0.067, 0.225; p=2.79Å~10−4) and reduced fasting glucose levels (β=−0.053; 95% CI −0.089, −0.017; p=4.31Å~10−3). However, there was little to no evidence of a direct protective effect on type 2 diabetes (OR 0.94; 95% CI 0.85, 1.04; p=0.228) independently of genetic liability to adulthood BMI. Conclusions/interpretation Our results provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty regarding the biological pathway of these effects and the limitations of this type of study

Determining how high body-mass index (BMI) at different time points influences the risk of developing type two diabetes (T2D), and affects insulin secretion and insulin sensitivity, is critical. 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 high adulthood BMI on the risk of T2D and insulin related phenotypes using Mendelian randomisation and studies of T2D, and oral and intravenous measures of insulin secretion and sensitivity. We found that a 1.s.d. (= 1.97kg/m2) higher childhood BMI, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including an increased insulin sensitivity index (β = 0.15 [0.067, 0.225], p = 2.79×10−4), and reduced fasting glucose (β = -0.053 [-0.089, -0.017], p = 4.31×10−3). There was however little to no evidence of a direct protective effect on T2D (OR = 0.94 [0.85 - 1.04], p = 0.228), independently of genetic liability to adulthood BMI. Our results thus cumulatively provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty in biological pathway of these effects, and the limitations of this type of study.Research in ContextHigh BMI in adulthood is associated with higher risk of type two diabetes, coupled with lower insulin sensitivity and secretion.Richardson et al [2020] used genetics to show that high BMI in childhood does not appear to increase the risk of type diabetes independently from its effect on adult BMI.We asked: does high childhood BMI affect insulin related traits such as fasting glucose and insulin sensitivity, independently of adulthood BMI?We used genetics to show that high childhood BMI has a protective effect on seven insulin sensitivity and secretion traits, including fasting glucose and measures of insulin sensitivity and secretion, independently of adulthood BMI.Our work has the potential to turn conventional understanding on its head – high BMI in childhood improves insulin sensitivity (when adjusting for knock on effects to high adult BMI) and opens up important questions about plasticity in childhood and compensatory mechanisms.

Background Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown. Aim We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. Methods We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. Results Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1–5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0–1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = −0.0019, P = 0.602). Conclusions Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DD), and have been shown to cause milder sub-clinical phenotypes in population cohorts. To investigate potential genetic modifiers, we identified individuals in UK Biobank with predicted deleterious variants in 599 autosomal dominant DD genes, and found that carrying multiple rare variants in these genes had an additive adverse effect on numerous cognitive and socio-economic traits, which could be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Amongst rare DD variant carriers, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may influence whether an individual reaches the threshold for clinical disease.

Evidence from observational studies suggests a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause-effect relationship is poorly understood, and these studies are susceptible to bias and confounding. Using Mendelian randomization (MR) methodology, this study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 participants in the UK Biobank. Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. We observed evidence of an inverse association between TSH levels and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that one standard deviation higher genetically instrumented TSH (approximately 0.8 mlU/L) resulted in an 80% reduction of risk of benign nodular disease (OR 0.20; 95% CI 0.10–0.41) and a 50% reduction of risk of thyroid cancer (OR 0.50; 95% CI 0.27–0.92). In keeping with other recently published studies, our results refute a causal role for TSH in both benign nodular thyroid disease and thyroid cancer, with increasing genetically instrumented TSH resulting in a lower risk of both diseases.

BackgroundPulmonary fibrosis (PF) is an incurable fibrotic lung disease with limited treatment options and a high mortality. Evidence is growing that short telomeres cause both heritable and idiopathic pulmonary fibrosis (IPF). Based on survival data, we hypothesised that sex hormones are protective against premature telomere attrition and could influence PF disease onset and/or progression.MethodsAssociations between IPF, sex hormone concentrations and measured leukocyte telomere length (LTL) were examined for unrelated UK Biobank participants of European ancestry with a diagnosis of IPF (415 females, 718 males) against controls (204,321 females, 174,254 males). Polygenic risk scores were used to explore causality between sex hormone indices, LTL and disease.FindingsStrong associations were found between IPF and LTL. For females, higher odds of having IPF was associated with early menopause and premature ovarian failure. Menopause age correlated positively with both age of IPF diagnosis and age of death. For males, IPF prevalence and stages of disease were associated with serum bioavailable testosterone concentrations. For both sexes, evidence of lower concentrations of sex hormones was associated with shorter LTL. Genetic analysis also inferred bi-directional causal links between sex hormone binding globulin concentration, which impacts free testosterone concentration, and LTL in males.InterpretationOur findings suggest that higher sex hormone concentrations protect against IPF onset and progression, possibly by slowing telomere shortening. Hormonal supplementation may delay or prevent disease onset for those with telomere-associated PF risk and improve disease prognosis. This warrants further exploration in a randomised controlled trial.FundingMedical Research Council.

Purpose: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. Methods: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. Results: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 x 10(-8)), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P Conclusion: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

This research has been conducted using the UK Biobank resource under application number 9072. Copyright © The Author(s) 2021. Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one-and two-sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß:-0.15, 95%CI:-0.26,-0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being. Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079 to J.O., F.C. and J.T.); Wellcome Senior Research Fellowship (WT220390 to R.M.F.). Diabetes UK RD Lawrence fellowship (17/0005594 to H.Y.).

Objectives To investigate the causal role of established risk factors and associated conditions to tinnitus and tinnitus severity in the UK Biobank. Design The prospective cohort study with large dataset of >500,000 individuals. The analytical sample of 129,731 individuals in the UK Biobank of European descent. Participants were recruited from National Health Service registries, baseline age range between 37 and 73 years, response rate to baseline survey 6%. Participants were asked subjective questions about tinnitus and its severity. Previously observed associations (n = 23) were confirmed in the UK Biobank using logistic and ordinal regression models. Two-sample Mendelian randomization approaches were then used to test causal relationships between the 23 predictors and tinnitus and tinnitus severity. The main outcome measures were observational and genetic association between key demographics and determinants and two tinnitus outcomes (current tinnitus and tinnitus severity). Results Prevalence of tinnitus was 20% and severe tinnitus 3.8%. The observational results are consistent with the previous literature, with hearing loss, older age, male gender, high BMI, higher deprivation, higher blood pressure, smoking history, as well as numerous comorbidities being associated with higher odds of current tinnitus. Mendelian randomization results showed causal correlations with tinnitus. Current tinnitus was predicted by genetically instrumented hearing loss (odds ratio [OR]: 8.65 [95% confidence interval (CI): 6.12 to 12.23]), major depression (OR: 1.26 [95% CI: 1.06 to 1.50]), neuroticism (OR: 1.48 [95% CI: 1.28 to 1.71]), and higher systolic blood pressure (OR: 1.01 [95% CI:1.00 to 1.02]). Lower odds of tinnitus were associated with longer duration in education (OR: 0.74 [95% CI: 0.63 to 0.88]), higher caffeine intake (OR: 0.89 [95% CI: 0.83 to 0.95]) and being a morning person (OR: 0.94 [95% CI: 0.90 to 0.98]). Tinnitus severity was predicted by a higher genetic liability to neuroticism (OR: 1.15 [95% CI: 1.06 to 1.26]) and schizophrenia (OR: 1.02 [95% CI: 1.00 to 1.04]). Conclusions Tinnitus data from the UK Biobank confirm established associated factors in the literature. Genetic analysis determined causal relationships with several factors that expand the understanding of the etiology of tinnitus and can direct future pathways of clinical care and research.

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 for80% 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.

Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00 g/dl increase in Hgb levels, was not associated (at P

BackgroundMenopausal vasomotor symptoms (VMS) significantly impact women’s quality of life, and whilst hormone replacement therapy (HRT) is effective, it is not appropriate for all. We aimed to identify new drug targets for VMS and understand reasons for HRT use through genomic analyses.MethodsIn up to 153,152 women from UK Biobank, a population-based cohort, we performed a genome-wide association study (GWAS) of VMS derived from linked primary-care records and cross-sectional self-reported data. In a subset of this cohort (n=39,356), we analysed exome-sequencing data to test the association of rare deleterious genetic variants with VMS. Finally, we used Mendelian randomisation analysis to investigate the reasons for HRT use and whether these changed over time.FindingsOur GWAS identified a genetic signal near the gene encoding NK3R (TACR3) associated with a lower risk of VMS (OR=0·85 (95% CI 0·82,0·87) per AT allele, P=1·1×10-26), which was consistent with previous studies. However, rare genetic variants predicted to reduce functional NK3R levels were not associated with VMS (P=0·9), though did delay puberty (P=9×10-11). Younger menopause age was causally-associated with greater HRT use before 2002 but not after.InterpretationUsing genomics we demonstrate that changed HRT use since the early 2000s reflects a switch from preventing post-menopausal complications to primarily treating VMS. We provide support for TACR3 in the genetic basis of VMS but unexpectedly find that rare genomic variants predicted to lower NK3R levels did not modify VMS, despite the proven efficacy of NK3R antagonists, suggesting that further biological understanding could benefit therapeutic efficacy.FundingCancer Research UK and UKRI.Research in contextEvidence before the studyIn vivo studies of animal models and clinical studies in humans have determined that menopausal vasomotor symptoms (VMS) result from increased neurokinin B (NKB) signalling via the neurokinin 3 receptor (NK3R) in response to decreased circulating oestradiol levels.Recent Phase II clinical trials have demonstrated the efficacy of NK3R antagonists in reducing VMS.A previous GWAS in 17,695 women identified a genetic signal at the TACR3 locus (which codes for NK3R) as associated with VMS. The locus was also genome-wide significant in a GWAS of oestrogen-replacement use (15,305 cases) derived from self-reported medications in UK Biobank.Added value of this studyThis study represents a novel approach to analysing the rarely captured phenotype of VMS, since few population-based cohorts have asked about menopausal symptoms.To the best of our knowledge, this is the first analyses of VMS identified from linked primary care health records. Literature searches of published papers and codelists have not identified any previous studies of VMS in primary care data. The replication of the known GWAS signal for VMS provides a validation of the coding of this phenotype from primary care data.This is the largest genomic study of VMS currently carried out (92,028 women). Our current analyses are limited by the availability of primary care linked data in ∼45% of the UK Biobank cohort and are based on exome sequencing in 200,000 women. Recently released exome data for the full cohort and further releases of primary care linked data in UK Biobank will allow us to re-visit these analyses further.Implications of all the available evidenceOur analyses of rare coding variation in TACR3 identified an intriguing difference that requires further study; while NK3R antagonist drug treatment reduces VMS, women carrying rare genetic variants resulting in reduced NK3R levels were no less likely to experience VMS.Our genome-wide analyses replicate the genetic signals for VMS at the TACR3 gene locus, however we were unable to unequivocally identify TACR3 as the causal gene at this locus.We suggest that the effect of the common genetic variant on reducing VMS may be through as yet uncharacterised regulatory pathways, and that complete inhibition of NK3R signalling is required to eliminate (rather than reduce) VMS.

BackgroundGene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panels vary in size, which affects the sensitivity and specificity of the test. We sought to investigate the background rate of candidate diagnostic variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases.MethodsWe used the Genotype-2-Phenotype database with the Variant Effect Predictor plugin to identify rare non-synonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated five clinically curated gene panels: developmental disorders (DD; 1708 genes), heritable eye disease (536 genes), skin disorders (293 genes), cancer syndromes (91 genes) and cardiac conditions (49 genes). We further tested the DD panel in 9,860 proband-parent trios from the Deciphering Developmental Disorders (DDD) study.ResultsAs expected, bigger gene panels resulted in more variants being prioritised, varying from an average of ∼0.3 per person in the smallest panels, to ∼3.5 variants per person using the largest panel. The number of individuals with prioritised variants varied linearly with coding sequence length for monoallelic disease genes (∼300 individuals per 1000 base pairs) and quadratically for biallelic disease genes, with some notable outliers. Based on cancer registry data from UK Biobank, there was no detectable difference between cases and controls in the number of individuals with prioritised variants using the cancer panel, presumably due to the predominance of sporadic disease. However, we observed a marked increase in the number of prioritised variants in the DD panel in the DDD study (∼5 variants per proband). Phasing of compound heterozygotes in biallelic genes resulted in a modest reduction in the number of prioritised variants.ConclusionsAlthough large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they will frequently prioritise false positive candidate variants potentially requiring additional clinical follow-up. Most individuals will have at least one rare nonsynonymous variant in panels containing >500 monogenic disease genes. Extreme caution should therefore be applied when interpreting potentially pathogenic variants found in the absence of relevant phenotypes.

Evidence from observational studies suggest a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause–effect relationship is poorly understood and these studies are susceptible to bias and confounding. This study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 UK Biobank participants, using a genetic technique, known as Mendelian randomization (MR). Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. Mendelian randomization provided evidence of a causal link between TSH and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that a 1 s.d. higher genetically instrumented TSH (approximately 0.8 mIU/L) resulted in 4.96-fold higher odds of benign nodular disease (95% CI 2.46–9.99) and 2.00-fold higher odds of thyroid cancer (95% CI 1.09–3.70). Our results thus support a causal role for TSH in both benign nodular thyroid disease and thyroid cancer.

Background Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD. Methods We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist–hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption. Results Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference. Conclusions These results provide strong evidence that a higher waist–hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.

Background Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and to test whether affected patients were genetically predisposed to multiple sclerosis [MS]. Methods We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 1219 patients exposed to anti-TNF who did not develop demyelination. Results Overall, 39 [74%] cases were female. The median age [range] of patients at time of demyelination was 41.5 years [20.7–63.2]. The median duration of anti-TNF treatment was 21.3 months [0.5-99.4] and 19 [36%] patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord, or both. Complete recovery was reported in 12 [23%] patients after a median time of 6.8 months [0.1–28.7]. After 33.0 months of follow-up, partial recovery was observed in 29 [55%] patients, relapsing and remitting episodes in nine [17%], progressive symptoms in three [6%]: two [4%] patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 × 10–4, standard deviation [SD] 0.0039) and controls [mean -1.1 × 10–3, SD 0.0042] [p = 0.23]. Conclusions Patients who experienced demyelination events following anti-TNF exposure were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not experience demyelination events. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.

BackgroundHuman birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables.MethodsWe analysed 549 European-ancestry parent-offspring trios. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics and parental anthropometric variables. We used R-Squared (R2) to estimate variance explained, adjusted R-squared (Adj-R2) to assess improvement in model fit from added predictors, and F-tests to compare nested models.ResultsMaternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R2 =0.233 vs Adj-R2=0.210, p2=0.264 vs 0.248, pConclusionsGenetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.Key messagesKnown contributors to variation in birthweight include (i) factors associated with the maternal intrauterine environment (e.g. maternal glycaemia or smoking), and (ii) parental heights, which capture some of the genetic contribution to fetal growth. However, the added contribution of genetic scores composed of common birthweight-associated variants has not been assessed.We showed, using 549 parent-offspring trios, that maternal and fetal genetic scores explained additional variation in sex-and gestational age-adjusted birthweight, when added to maternal variables that are easily obtained in a clinical setting (age, weight, smoking, parity and 28-week fasting glucose).Parental heights explained variance in birthweight independently of routinely measured maternal clinical variables, but the maternal and fetal (or paternal) genetic scores made additional, independent contributions to birthweight variance.The genetic score contribution was modest, but it was comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.Since this work was limited to a UK sample of European ancestry, it will, however, be important to test the relative contributions of genetics and other factors to birthweight variation in diverse populations.

Size at birth is known to be influenced by various fetal and maternal factors including genetic effects. South Asians have a high burden of low birthweight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic score (fGS) and maternal genetic score (mGS) from 196 birthweight-associated variants identified in Europeans and conducted association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6 years’ intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from above cohorts were compared with South Asians in UK BioBank and The Exeter Family Study of Childhood Health, a European ancestry cohort. Birthweight increased by 50.7g and 33.6g per standard deviation of fGS (p = 9.1x10-11) and mGS (p = 0.003) respectively in South Asians. A relatively weaker maternal genetic score effect compared to Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birthweight was strongly associated with body size in both childhood and adolescence (p = 3x10-5 - 1.9x10-51), however, fetal genetic score was associated with body size in childhood only (p < 0.01) and with head circumference, fasting glucose and triglycerides in adults (p < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birthweight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism partly explaining associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians.

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.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P

Many rare diseases are known to be caused by deleterious variants in Mendelian 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 that are known to cause monogenic developmental disorders (DD) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 dominant DD genes using whole exome sequencing data from ∼200,000 individuals, and rare copy number variants overlapping known DD loci 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, with a higher BMI and had significant socioeconomic disadvantages, being less likely to be employed or be able to work, and having a lower income and higher deprivation index. Our findings suggest that many monogenic DD genes routinely tested within paediatric genetics have intermediate penetrance and may cause lifelong milder, sub-clinical phenotypes in the general adult 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.

Data availability: Our study uses two-sample MR. We used both published summary results (i.e. taking results from published research papers and websites) and individual participant cohort data: journal-published and website summary data were used for sample one of the two-sample MR (published GWAS of BMI and body fat percentage). The references to the published data sources are provided in the main paper. The data for the GWAS of BMI are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files. The data for the GWAS of body fat percentage are available at https://walker05.u.hpc.mssm.edu. We used individual participant data for the second MR sample and for undertaking sensitivity analyses from the UKB, ALSPAC, BiB, EFSOCH and HAPO cohorts. The data in UKB, ALSPAC and BiB are fully available, via managed systems, to any researchers. The managed system for both studies is a requirement of the study funders but access is not restricted on the basis of overlap with other applications to use the data or on the basis of peer review of the proposed science. Researchers have to pay for a dataset to be prepared for them. Full information on how to access UKB data can be found at www.ukbiobank.ac.uk/using-the-resource/. The ALSPAC data management plan (www.bristol.ac.uk/alspac/researchers/data-access/documents/alspac-data-management-plan.pdf) describes, in detail, the policy regarding data sharing, which is through a system of managed open access. The following steps highlight how to apply for access to the data included in this paper and all other ALSPAC data: (1) please read the ALSPAC access policy (PDF, 627 kB), which describes the process of accessing the data and samples in detail, and outlines the costs associated with doing so; (2) you may also find it useful to browse the fully searchable ALSPAC research proposals database, which lists all research projects that have been approved since April 2011; (3) please submit your research proposal for consideration by the ALSPAC Executive Committee and you will receive a response within 10 working days to advise you whether your proposal has been approved. If you have any questions about accessing data, please e-mail alspac-data@bristol.ac.uk. Full information on how to access BiB data can be found at https://borninbradford.nhs.uk/research/how-to-access-data/. Requests for access to the original EFSOCH dataset should be made in writing in the first instance to the EFSOCH data team via the Exeter Clinical Research Facility (crf@exeter.ac.uk). Copyright © The Author(s) 2022. Aims/hypothesis: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal ‘metabolically favourable adiposity’ on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI). Methods: To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-sample MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI (n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects (n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother–child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers. Results: Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (−94 [95% CI −150, −38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m2] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures; their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller sample sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it. Conclusions/interpretation: Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile. US National Institute of Health (R01 DK10324); European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545; British Heart Foundation (CS/16/4/32482 and AA/18/7/34219); NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust; University of Bristol.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5,485 women with GDM and 347,856 without GDM. Through trans-ancestry meta-analysis, we identified five loci with genome-wide significant association (p−8) with GDM, mapping to/near MTNR1B (p=4.3×10−54), TCF7L2 (p=4.0×10−16), CDKAL1 (p=1.6×10−14), CDKN2A-CDKN2B (p=4.1×10−9) and HKDC1 (p=2.9×10−8). Multiple lines of evidence pointed to genetic contributions to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.