scholarly journals Study of association of migraine susceptibility genes with common migraine in 200,000 exome-sequenced UK Biobank participants

2021 ◽  
Author(s):  
Katherine Alexis Markel ◽  
David Curtis
Keyword(s):  
Migraine With Aura ◽  
Susceptibility Genes ◽  
Uk Biobank ◽  
Functional Variants ◽  
Number Of Genes ◽  
The Common ◽  
The Uk ◽  
Tests For Association

AbstractBackgroundA number of genes have been implicated in rare familial syndromes which have migraine as part of their phenotype but these genes have not previously been implicated in the common form of migraine.MethodsAmong exome-sequenced participants in the UK Biobank we identified 7,194 migraine cases with the remaining 193,433 participants classified as controls. We investigated ten genes previously reported to be implicated in conditions with migraine as a prominent part of the phenotype and carried out gene and variant based tests for association.ResultsWe found no evidence for association of these genes or variants with the common form of migraine seen in our subjects. In particular, a frameshift variant in KCNK18, F139Wfs*24, which had been shown to segregate with migraine with aura in a multiply affected pedigree was found in 196 (0.10%) controls as well as in 10 (0.14%) cases (χ2 = 0.96, 1 df, p = 0.33).ConclusionsSince there is no other reported evidence to implicate KCNK18, we conclude that this gene and its product, TRESK, should no longer be regarded as being involved in migraine aetiology. Overall, we do not find that rare, functional variants in genes previously implicated to be involved in familial syndromes including migraine as part of the phenotype make a contribution to the commoner forms of migraine observed in this population.

scholarly journals Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

2019 ◽  
Vol 116 (21) ◽  
pp. 10430-10434 ◽  
Author(s):  
Gaspard Kerner ◽  
Noe Ramirez-Alejo ◽  
Yoann Seeleuthner ◽  
Rui Yang ◽  
Masato Ogishi ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Genetic Basis ◽  
Sub Saharan Africa ◽  
European Ancestry ◽  
Uk Biobank ◽  
The United Kingdom ◽  
The Common ◽  
Sub Saharan ◽  
The Uk ◽  
High Level

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96–10.31, P = 2 × 10−3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.

scholarly journals Accurate Genomic Prediction Of Human Height

2017 ◽  
Author(s):  
Louis Lello ◽  
Steven G. Avery ◽  
Laurent Tellier ◽  
Ana I. Vazquez ◽  
Gustavo de los Campos ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Uk Biobank ◽  
Multiple Phenotypes ◽  
Human Height ◽  
Out Of Sample ◽  
Heel Bone ◽  
The Common ◽  
Actual Height ◽  
The Uk ◽  
Missing Heritability Problem

AbstractWe construct genomic predictors for heritable and extremely complex human quan-titative traits (height, heel bone density, and educational attainment) using modern methods in high dimensional statistics (i.e., machine learning). Replication tests show that these predictors capture, respectively, ∼40, 20, and 9 percent of total variance for the three traits. For example, predicted heights correlate ∼0.65 with actual height; actual heights of most individuals in validation samples are within a few cm of the prediction. The variance captured for height is comparable to the estimated SNP heritability from GCTA (GREML) analysis, and seems to be close to its asymptotic value (i.e., as sample size goes to infinity), suggesting that we have captured most of the heritability for the SNPs used. Thus, our results resolve the common SNP portion of the “missing heritability” problem – i.e., the gap between prediction R-squared and SNP heritability. The ∼20k activated SNPs in our height predictor reveal the genetic architecture of human height, at least for common SNPs. Our primary dataset is the UK Biobank cohort, comprised of almost 500k individual genotypes with multiple phenotypes. We also use other datasets and SNPs found in earlier GWAS for out-of-sample validation of our results.

scholarly journals ApoE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort

2020 ◽  
Author(s):  
Chia-Ling Kuo ◽  
Luke C Pilling ◽  
Janice L Atkins ◽  
Jane AH Masoli ◽  
João Delgado ◽  
...  
Keyword(s):  
Older Adults ◽  
Risk Factor ◽  
High Risk ◽  
The Novel ◽  
Shortness Of Breath ◽  
Uk Biobank ◽  
Impaired Consciousness ◽  
Homozygous Genotype ◽  
The Common ◽  
The Uk

The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that pre-existing dementia is a major risk factor (OR = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 hospitalization in the UK Biobank (UKB). In another UK study of 16,749 patients hospitalized for COVID-19, dementia was among the common comorbidities and was associated with higher mortality. Additionally, impaired consciousness, including delirium, is common in severe cases. The ApoE e4 genotype is associated with both dementia and delirium, with the e4e4 (homozygous) genotype associated with high risk of dementia. We therefore aimed to test associations between ApoE e4 alleles and COVID-19 severity, using the UKB data.

scholarly journals Weighted burden analysis in 200 000 exome-sequenced UK Biobank subjects characterises effects of rare genetic variants on BMI

2021 ◽  
Author(s):  
David Curtis
Keyword(s):  
Multiple Testing ◽  
Rare Variants ◽  
Sequence Data ◽  
Statistical Significance ◽  
Positive Sign ◽  
P Value ◽  
Uk Biobank ◽  
Functional Variants ◽  
Rare Genetic Variants ◽  
The Uk

AbstractIntroductionA number of genes have been identified in which rare variants can cause obesity. Here we analyse a sample of exome sequenced subjects from UK Biobank using BMI as a phenotype.MethodsThere were 199,807 exome sequenced subjects for whom BMI was recorded. Weighted burden analysis of rare, functional variants was carried out, incorporating population principal components and sex as covariates. For selected genes, additional analyses were carried out to clarify the contribution of different categories of variant. Statistical significance was summarised as the signed log 10 of the p value (SLP), given a positive sign if the weighted burden score was positively correlated with BMI.ResultsTwo genes were exome-wide significant, MC4R (SLP = 15.79) and PCSK1 (SLP = 6.61). In MC4R, disruptive variants were associated with an increase in BMI of 2.72 units and probably damaging nonsynonymous variants with an increase of 2.02 units. In PCSK1, disruptive variants were associated with a BMI increase of 2.29 and protein-altering variants with an increase of 0.34. Results for other genes were not formally significant after correction for multiple testing, although SIRT1, ZBED6 and NPC2 were noted to be of potential interest.ConclusionBecause the UK Biobank consists of a self-selected sample of relatively healthy volunteers, the effect sizes noted may be underestimates. The results demonstrate the effects of very rare variants on BMI and suggest that other genes and variants will be definitively implicated when the sequence data for additional subjects becomes available.This research has been conducted using the UK Biobank Resource.

scholarly journals Multiple linear regression allows weighted burden analysis of rare coding variants in an ethnically heterogeneous population

2020 ◽  
Author(s):  
David Curtis
Keyword(s):  
Linear Regression ◽  
Principal Components ◽  
Rare Variants ◽  
Linear Regression Analysis ◽  
Uk Biobank ◽  
Case Control Studies ◽  
Test Statistic ◽  
Functional Variants ◽  
The Uk ◽  
Coding Variants

AbstractWeighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using BMI as the phenotype the method produces a very inflated test statistic. However this is almost completely corrected by including 20 population principal components as covariates. When this is done the top 30 genes include a few which are quite plausibly associated with the phenotype, including LYPLAL1 and NSDHL. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.

scholarly journals Association of the Transthyretin Variant V122I With Polyneuropathy Among Individuals of African Descent

2020 ◽  
Author(s):  
Margaret M. Parker ◽  
Scott M. Damrauer ◽  
Catherine Tcheandjieu ◽  
David Erbe ◽  
Emre Aldinc ◽  
...  
Keyword(s):  
Cox Regression ◽  
African Descent ◽  
Gene Mutations ◽  
Uk Biobank ◽  
Cardiac Phenotype ◽  
Diagnosis Codes ◽  
Increased Risk ◽  
Tunnel Syndrome ◽  
The Common ◽  
The Uk

BACKGROUNDHereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating disease caused by transthyretin (TTR) gene mutations. The V122I variant, a common pathogenic TTR mutation found primarily in individuals of West African descent, is frequently associated with cardiomyopathy.METHODSThe association between the V122I variant and ICD10 diagnosis codes was assessed in the UK Biobank black subpopulation (N=6062); whether significant associations could be replicated in the Penn Medicine Biobank (N=5737) and Million Veteran Program (N=82,382) was then investigated. Cumulative incidence of common hATTR amyloidosis manifestations (polyneuropathy, carpal tunnel syndrome, cardiomyopathy, and heart failure) was estimated by V122I genotype in the UK Biobank using Cox regression controlling for age, sex, and genetic ancestry.RESULTSPhenome-wide analysis identified a significant association between V122I genotype and polyneuropathy diagnosis (odds ratio [OR]=6.4, 95% confidence interval [CI]=2.6–15.6, P=4.2×10−5) in the UK Biobank. A significant association was also observed in the Penn Medicine Biobank (OR=1.6, 95% CI=1.2–2.4, P=6.0×10−3) and the Million Veteran Program (OR=1.5, 95% CI=1.2–1.8, P=1.8×10−4). Prevalence of a polyneuropathy diagnosis among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. In the UK Biobank, common hATTR amyloidosis manifestations were significantly enriched in V122I carriers compared with non-carriers (HR=2.8; 95% CI=1.7–4.5; P=2.6×10−5). By age 75, 37.4% of V122I carriers had a diagnosis of any one of the common manifestations, including polyneuropathy (7.9%).CONCLUSIONSV122I carriers, historically associated with a predominantly cardiac phenotype of hATTR amyloidosis, have a significantly increased risk of polyneuropathy.

scholarly journals Multiple Linear Regression Allows Weighted Burden Analysis of Rare Coding Variants in an Ethnically Heterogeneous Population

2021 ◽  
pp. 1-10
Author(s):  
David Curtis
Keyword(s):  
Linear Regression ◽  
Principal Components ◽  
Rare Variants ◽  
Linear Regression Analysis ◽  
Uk Biobank ◽  
Case Control Studies ◽  
Test Statistic ◽  
Functional Variants ◽  
The Uk ◽  
Coding Variants

Weighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates, such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using body mass index as the phenotype, the method produces a very inflated test statistic. However, this is almost completely corrected by including 20 population principal components as covariates. When this is done, the top 30 genes include a few which are quite plausibly associated with the phenotype, including <i>LYPLAL1</i> and <i>NSDHL</i>. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.

Low birthweight is associated with poorer limb muscle mass and grip strength in middle age: findings from the UK Biobank Imaging Enhancement

2019 ◽  
Author(s):  
Elizabeth Curtis ◽  
Justin Liu ◽  
Kate Ward ◽  
Karen Jameson ◽  
Zahra Raisi-Estabragh ◽  
...  
Keyword(s):  
Grip Strength ◽  
Muscle Mass ◽  
Low Birthweight ◽  
Middle Age ◽  
Limb Muscle ◽  
Uk Biobank ◽  
The Uk
Sign in / Sign up

Export Citation Format

Share Document