Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population

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.

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Recent Caffeine Drinking Associates with Cognitive Function in the UK Biobank

Nutrients ◽

10.3390/nu12071969 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1969

Author(s):

Marilyn C. Cornelis ◽

Sandra Weintraub ◽

Martha Clare Morris

Keyword(s):

Cognitive Function ◽

Fluid Intelligence ◽

Real Life ◽

Reaction Times ◽

Sociodemographic Factors ◽

Test Time ◽

Caffeine Intake ◽

Uk Biobank ◽

Caffeine Metabolism ◽

The Impact

Clinical evidence points to the premise that caffeine may benefit cognition, but whether these findings extend to real life settings and amidst factors that impact caffeine metabolism is unclear. The aim of this study was to investigate the impact of recent caffeine drinking on cognitive ability while additionally accounting for lifestyle and genetic factors that impact caffeine metabolism. We included up to 434,900 UK Biobank participants aged 37–73 years, recruited in 2006–2010, who provided biological samples and completed touchscreen questionnaires regarding sociodemographic factors, medical history, lifestyle, and diet. Recent caffeine drinking (yes/no in the last hour) was recorded during a physical assessment. Participants completed at least one of four self-administered cognitive function tests using the touchscreen system: prospective memory (PM), pairs matching (Pairs), fluid intelligence (FI), and reaction time (RT). Multivariable regressions were used to examine the association between recent caffeine drinking and cognition test scores. We also tested interactions between recent caffeine drinking and a genetic caffeine-metabolism score (CMS) on cognitive function. Among white participants, recent caffeine drinking was associated with higher performance on RT but lower performance on FI, Pairs, and PM (p ≤ 0.004). Similar directions of associations for FI (p = 0.09), Pairs (p = 0.03), and PM (p = 0.34) were observed among non-white participants. No significant and consistent effect modification by age, sex, smoking, test time, habitual caffeine intake, or CMS was observed. Caffeine consumed shortly before tasks requiring shorter reaction times may improve task performance. Potential impairments in memory and reasoning tasks with recent caffeine drinking warrant further study.

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Prodromal Progressive Supranuclear Palsy: insights from the UK Biobank

10.1101/2021.05.06.21256759 ◽

2021 ◽

Author(s):

Duncan Street ◽

David Whiteside ◽

Timothy Rittman ◽

James Rowe

Keyword(s):

Progressive Supranuclear Palsy ◽

Fluid Intelligence ◽

Reaction Times ◽

Uk Biobank ◽

Diagnostic Features ◽

Parkinsons Disease ◽

Diagnostic Coding ◽

Time To Diagnosis ◽

Digit Recall ◽

The Uk

Background: Prodromal Parkinsons Disease is well described but prodromal Progressive Supranuclear Palsy (PSP) is much less understood. The diagnosis of PSP is typically delayed by an average of three years after symptom onset. Understanding the changes that occur in the prodromal and prediagnostic period will aid earlier diagnosis, clarify the natural history, and aid the design of early disease modifying therapy trials. Objectives: To determine motor and cognitive markers of prodromal PSP, with Parkinsons disease as a comparator condition, in a large prospective cohort. Methods: Baseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinsons disease cases were identified from primary and secondary care electronic health records diagnostic coding data and death registry, with 5,404 matched controls. Results: 176 PSP cases (mean [SD] time to diagnosis 7.8 [2.8] years) and 2,526 Parkinsons disease cases (time to diagnosis 7.8 [2.9] years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, poorer prospective memory, worse self rated health score and lower digit recall than controls. They had higher mortality than both Parkinsons disease and control groups. Conclusions: Motor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP and are typically symptomatic three years before diagnosis. However, objective markers of these features are evident over seven years before diagnosis. This suggests a long prodromal course in PSP with subtle changes in motor and cognitive function.

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MO042PREVALENCE OF FABRY DISEASE CAUSING VARIANTS IN THE UK BIOBANK

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab080.0014 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Mark Gilchrist ◽

Francesco Casanova ◽

Jessica Tyrrell ◽

Nicole Fife ◽

Katie Young ◽

...

Keyword(s):

Fabry Disease ◽

Clinical Care ◽

Adult Population ◽

Renal Involvement ◽

Population Sample ◽

Clinical Manifestations ◽

Uk Biobank ◽

Sequencing Data ◽

Gastrointestinal Pathology ◽

The Uk

Abstract Background and Aims Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from deficiency of the alpha-galactosidase A enzyme. This leads to the accumulation of globotriaosylceramide in multiple organ sites with prominent renal involvement, cardio and cerebrovascular disease, as well as neurological, dermatological, and gastrointestinal pathology in affected individuals. Clinical manifestations are highly heterogeneous with considerable variation depending on the specific variant and even within families with the same variant. Prevalence estimates from studies of case control cohorts range from 1 in 40,000 to 1 in 140,000. We sought to determine the prevalence of Fabry disease causing mutations in an unbiased adult population sample using the UK Biobank. Method UK Biobank comprises approximately 500,000 participants with extensive phenotyping and genetic data linked to clinical care records. Exome sequencing data from 200643 individuals from the UK Biobank were examined for variants in the GLA gene. Likely mutations were searched for in ClinVar and HGMD with subsequent review of supporting literature. We used ACMG guidelines to classify the pathogenicity of variants. Results Eighty one coding variants were identified in GLA. Nine of these variants were rare (<1 in 10,000 individuals) and either protein truncating variants or previously reported to cause Fabry’s disease. Thirty seven individuals, (14 males, 22 females, 1 missing data) carried one of these GLA variants. The most common variant was the cardiac predominant phenotype causing N215S variant (18/37). 6/37 had the R363C variant, 4/37 had R356Q. The R112H, R301Q, I198T variants were each identified in 2 individuals. There were single individuals with I232T, K240fs, and E66G variants. Two male individuals (with I232T, K240fs variants) had HES codes compatible with a known diagnosis of Fabry disease. The remaining 12/14 males did not have evidence of an existing diagnosis of Fabry disease. No female participants had HES codes indicating an existing diagnosis of Fabry disease. The overall prevalence of Fabry disease causing variants in the UK Biobank is 1 in 5,422. The N215 variant alone has a prevalence of 1 in 11,147. Conclusion Reported Fabry disease causing GLA variants are far more prevalent in an unselected population sample than would be expected from the reported prevalence of Fabry disease. This may be because some of the reported variants are not pathogenic, or are predominantly later-onset causing variants with reduced penetrance. The true prevalence of Fabry disease may be substantially higher than current estimates.

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Mosaic Turner syndrome shows reduced phenotypic penetrance in an adult population study compared to clinically ascertained cases

10.1101/177659 ◽

2017 ◽

Cited By ~ 5

Author(s):

Marcus A. Tuke ◽

Katherine S. Ruth ◽

Andrew R. Wood ◽

Robin N. Beaumont ◽

Jessica Tyrrell ◽

...

Keyword(s):

Turner Syndrome ◽

X Chromosome ◽

Disease Risk ◽

Adult Population ◽

Cardiovascular Disease Risk ◽

Large Population ◽

Snp Array ◽

Age At Menarche ◽

Chromosome Aneuploidy ◽

Triple X Syndrome

AbstractWomen with X chromosome aneuploidy such as 45,X (Turner syndrome) or 47,XXX (Triple X syndrome) present with characteristics including differences in stature, increased cardiovascular disease risk and primary ovarian insufficiency. Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the phenotypic penetrance is overestimated. Studies of prenatally ascertained X chromosome aneuploidy cases have limited follow-up data and so the long-term consequences into adulthood are often not reported. We aimed to characterise the prevalence and phenotypic consequences of X chromosome aneuploidy in a large population of women over 40 years of age. We detected 30 women with 45,X, 186 with mosaic 45,X/46,XX and 110 with 47,XXX among 244,848 UK Biobank women, using SNP array data. The prevalence of non-mosaic 45,X (1/8,162) and 47,XXX (1/2,226) was lower than expected, but was higher for mosaic 45,X/46,XX (1/1,316). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognised Turner syndrome phenotype, including a 17.2cm shorter stature (SD = 5.72cm; P = 1.5 × 10−53) and 16/30 did not report an age at menarche. The phenotype of women with 47,XXX included taller stature (5.3cm; SD = 5.52cm; P = 5.8 × 10−20), earlier menopause age (5.12 years; SD = 5.1 years; P = 1.2 x 10−14) and a lower fluid intelligence score (24%; SD = 29.7%; P = 3.7 × 10−8). In contrast, the characteristics of women with mosaic 45,X/46,XX were much less pronounced than expected. Women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. In conclusion, the availability of data from 244,848 women allowed us to assess the phenotypic penetrance of traits associated with X chromosome aneuploidy in an adult population setting. Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.FundingNone

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Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

BMJ ◽

10.1136/bmj.n214 ◽

2021 ◽

pp. n214

Author(s):

Weedon MN ◽

Jackson L ◽

Harrison JW ◽

Ruth KS ◽

Tyrrell J ◽

...

Keyword(s):

Positive Predictive Value ◽

Predictive Value ◽

Population Based ◽

Genome Project ◽

Personal Genome ◽

Uk Biobank ◽

Sequencing Data ◽

Snp Chip ◽

Pathogenic Variants ◽

The Uk

Abstract Objective To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. Design Retrospective, population based diagnostic evaluation. Participants 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. Main outcome measures Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

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Evaluating the genetic effects of sex hormone traits on the development of mental traits: a polygenic score analysis and gene-environment-wide interaction study in UK Biobank cohort

Molecular Brain ◽

10.1186/s13041-020-00718-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Xiao Liang ◽

ShiQiang Cheng ◽

Jing Ye ◽

XiaoMeng Chu ◽

Yan Wen ◽

...

Keyword(s):

Alcohol Consumption ◽

Fluid Intelligence ◽

Genetic Effects ◽

Sex Hormone ◽

Uk Biobank ◽

Interaction Study ◽

Middle Aged ◽

Bioavailable Testosterone ◽

Gene Environment ◽

Middle Aged Adults

Abstract Objective To evaluate the genetic effects of sex hormone traits on the development of mental traits in middle-aged adults. Methods The SNPs associated with sex hormone traits were derived from a two-stage genome-wide association study (GWAS). Four sex hormone traits were selected in the current study, including sex hormone-binding globulin (SHBG), testosterone, bioavailable testosterone and estradiol. The polygenic risk score (PRS) of sex hormone traits were calculated from individual-level genotype data of the United Kingdom (UK) Biobank cohort. We then used logistic and linear regression models to assess the associations between individual PRS of sex hormone traits and the frequency of alcohol consumption, anxiety, intelligence and so on. Finally, gene-environment-wide interaction study (GEWIS) was performed to detect novel candidate genes interacting with the sex hormone traits on the development of fluid intelligence and the frequency of smoking and alcohol consumption by PLINK2.0. Results We observed positive association between SHBG and the frequency of alcohol consumption (b = 0.0101, p = 3.84 × 10–11) in middle-aged males and females. In addition, estradiol was positively associated with the frequency of alcohol consumption (b = 0.0128, p = 1.96 × 10–8) in middle-aged males. Moreover, bioavailable testosterone was associated with the fluid intelligence (b = − 0.0136, p = 5.74 × 10–5) in middle-aged females. Finally, GEWIS identified one significant loci, Tenascin R (TNR) (rs34633780, p = 3.45 × 10–8) interacting with total testosterone for fluid intelligence. Conclusion Our study results support the genetic effects of sex hormone traits on the development of intelligence and the frequency of alcohol consumption in middle-aged adults in UK.

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QTL mapping of root traits in wheat under different phosphorus levels using hydroponic culture

BMC Genomics ◽

10.1186/s12864-021-07425-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Mengjiao Yang ◽

Cairong Wang ◽

Muhammad Adeel Hassan ◽

Faji Li ◽

Xianchun Xia ◽

...

Keyword(s):

Root System ◽

Phenotypic Diversity ◽

Nutrient Use Efficiency ◽

Snp Array ◽

P Uptake ◽

Hydroponic Culture ◽

Seedling Stage ◽

Root Surface Area ◽

Root Tips ◽

Phenotypic Effect

Abstract Background Phosphorus (P) is an important in ensuring plant morphogenesis and grain quality, therefore an efficient root system is crucial for P-uptake. Identification of useful loci for root morphological and P uptake related traits at seedling stage is important for wheat breeding. The aims of this study were to evaluate phenotypic diversity of Yangmai 16/Zhongmai 895 derived doubled haploid (DH) population for root system architecture (RSA) and biomass related traits (BRT) in different P treatments at seedling stage using hydroponic culture, and to identify QTL using 660 K SNP array based high-density genetic map. Results All traits showed significant variations among the DH lines with high heritabilities (0.76 to 0.91) and high correlations (r = 0.59 to 0.98) among all traits. Inclusive composite interval mapping (ICIM) identified 34 QTL with 4.64–20.41% of the phenotypic variances individually, and the log of odds (LOD) values ranging from 2.59 to 10.43. Seven QTL clusters (C1 to C7) were mapped on chromosomes 3DL, 4BS, 4DS, 6BL, 7AS, 7AL and 7BL, cluster C5 on chromosome 7AS (AX-109955164 - AX-109445593) with pleiotropic effect played key role in modulating root length (RL), root tips number (RTN) and root surface area (ROSA) under low P condition, with the favorable allele from Zhongmai 895. Conclusions This study carried out an imaging pipeline-based rapid phenotyping of RSA and BRT traits in hydroponic culture. It is an efficient approach for screening of large populations under different nutrient conditions. Four QTL on chromosomes 6BL (2) and 7AL (2) identified in low P treatment showed positive additive effects contributed by Zhongmai 895, indicating that Zhongmai 895 could be used as parent for P-deficient breeding. The most stable QTL QRRS.caas-4DS for ratio of root to shoot dry weight (RRS) harbored the stable genetic region with high phenotypic effect, and QTL clusters on 7A might be used for speedy selection of genotypes for P-uptake. SNPs closely linked to QTLs and clusters could be used to improve nutrient-use efficiency.

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High-throughput inference of pairwise coalescence times identifies signals of selection and enriched disease heritability

10.1101/276931 ◽

2018 ◽

Cited By ~ 3

Author(s):

Pier Francesco Palamara ◽

Jonathan Terhorst ◽

Yun S. Song ◽

Alkes L. Price

Keyword(s):

Positive Selection ◽

Snp Array ◽

Complex Trait ◽

Joint Analysis ◽

Background Selection ◽

Sequencing Data ◽

Data Set ◽

Coalescence Time ◽

Recent Positive Selection ◽

Coalescence Times

AbstractInterest in reconstructing demographic histories has motivated the development of methods to estimate locus-specific pairwise coalescence times from whole-genome sequence data. We developed a new method, ASMC, that can estimate coalescence times using only SNP array data, and is 2-4 orders of magnitude faster than previous methods when sequencing data are available. We were thus able to apply ASMC to 113,851 phased British samples from the UK Biobank, aiming to detect recent positive selection by identifying loci with unusually high density of very recent coalescence times. We detected 12 genome-wide significant signals, including 6 loci with previous evidence of positive selection and 6 novel loci, consistent with coalescent simulations showing that our approach is well-powered to detect recent positive selection. We also applied ASMC to sequencing data from 498 Dutch individuals (Genome of the Netherlands data set) to detect background selection at deeper time scales. We observed highly significant correlations between average coalescence time inferred by ASMC and other measures of background selection. We investigated whether this signal translated into an enrichment in disease and complex trait heritability by analyzing summary association statistics from 20 independent diseases and complex traits (average N=86k) using stratified LD score regression. Our background selection annotation based on average coalescence time was strongly enriched for heritability (p = 7×10−153) in a joint analysis conditioned on a broad set of functional annotations (including other background selection annotations), meta-analyzed across traits; SNPs in the top 20% of our annotation were 3.8x enriched for heritability compared to the bottom 20%. These results underscore the widespread effects of background selection on disease and complex trait heritability.

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Integrative DNA copy number detection and genotyping from sequencing and array-based platforms

10.1101/172700 ◽

2017 ◽

Cited By ~ 2

Author(s):

Zilu Zhou ◽

Weixin Wang ◽

Li-San Wang ◽

Nancy Ruonan Zhang

Keyword(s):

Copy Number ◽

Association Studies ◽

Snp Array ◽

Supplementary Information ◽

Detection Accuracy ◽

Sequencing Data ◽

Array Data ◽

Combining Data ◽

Allele Specific ◽

Cnv Detection

AbstractMotivationCopy number variations (CNVs) are gains and losses of DNA segments and have been associated with disease. Many large-scale genetic association studies are performing CNV analysis using whole exome sequencing (WES) and whole genome sequencing (WGS). In many of these studies, previous SNP-array data are available. An integrated cross-platform analysis is expected to improve resolution and accuracy, yet there is no tool for effectively combining data from sequencing and array platforms. The detection of CNVs using sequencing data alone can also be further improved by the utilization of allele-specific reads.ResultsWe propose a statistical framework, integrated Copy Number Variation detection algorithm (iCNV), which can be applied to multiple study designs: WES only, WGS only, SNP array only, or any combination of SNP and sequencing data. iCNV applies platform specific normalization, utilizes allele specific reads from sequencing and integrates matched NGS and SNP-array data by a Hidden Markov Model (HMM). We compare integrated two-platform CNV detection using iCNV to naive intersection or union of platforms and show that iCNV increases sensitivity and robustness. We also assess the accuracy of iCNV on WGS data only, and show that the utilization of allele-specific reads improve CNV detection accuracy compared to existing methods.Availabilityhttps://github.com/zhouzilu/[email protected], [email protected] informationSupplementary data are available at Bioinformatics online.

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Human genetic evidence supports MAP3K15 inhibition as a therapeutic strategy for diabetes

10.1101/2021.11.14.21266328 ◽

2021 ◽

Author(s):

Abhishek Nag ◽

Ryan Dhindsa ◽

Andrew R. Harper ◽

Dimitrios Vitsios ◽

Andrea Ahnmark ◽

...

Keyword(s):

Adult Population ◽

Tissue Expression ◽

Chronic Health Condition ◽

Genetic Evidence ◽

Uk Biobank ◽

Genetic Associations ◽

Pancreatic Islet Cell ◽

Resistance Pathway ◽

Increased Risk ◽

Reduced Risk

Diabetes mellitus is a chronic health condition that can result in significant end-organ complications and is estimated to impact at least 8.5% of the global adult population. Here, we performed gene-level collapsing analysis on exome sequences from 454,796 multi-ancestry UK Biobank participants to detect genetic associations with diabetes. Rare nonsynonymous variations in GCK, GIGYF1, HNF1A, and HNF4A were significantly associated (P<1x10-8) with increased risk of diabetes, whereas rare nonsynonymous variations in MAP3K15 were significantly associated with reduced risk of diabetes. Recessive carriers of rare non-synonymous variants in the X chromosome gene MAP3K15 had a 30% reduced risk of diabetes (OR=0.70, 95% CI: [0.62,0.79], P=5.7x10-10), along with reduced blood glucose (beta=-0.13, 95% CI: [-0.15,-0.10], P=5.5x10-18) and reduced glycosylated haemoglobin levels (beta=-0.14, 95% CI: [-0.16,-0.11], P=1.1x10-24). Hemizygous males carrying protein-truncating variants (PTVs) in MAP3K15 demonstrated a 40% reduced risk of diabetes (OR=0.60, 95% CI: [0.45,0.81], P=0.0007). These findings were independently replicated in FinnGen, with a MAP3K15 PTV associating with decreased risk of both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) (p<0.05). The effect of MAP3K15 loss on diabetes was independent of body mass index, suggesting its protective effect is unlikely to be mediated via the insulin resistance pathway. Tissue expression profile of MAP3K15 indicates a possible involvement of pancreatic islet cell or stress response pathways. No safety concerns were identified among heterozygous or recessive MAP3K15 PTV carriers across over 15,719 studied endpoints in the UK Biobank. Human population genetic evidence supports MAP3K15 inhibition as a novel therapeutic target for diabetes.

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