Contrasting Broad- and Clinically- defined Polygenic Indicators of Depression and Depression-related Phenotypes in Adults and Children

2020 ◽  
Author(s):  
John E. McGeary ◽  
Chelsie Benca-Bachman ◽  
Victoria Risner ◽  
Christopher G Beevers ◽  
Brandon Gibb ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Cognitive Reappraisal ◽  
Twin Studies ◽  
European Ancestry ◽  
Summary Statistics ◽  
Depression Severity ◽  
Uk Biobank ◽  
Polygenic Scores ◽  
Adults And Children ◽  
The Uk

Twin studies indicate that 30-40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank using independent cohorts of adults (N=210; 100% European Ancestry) and children (N=728; 70% European Ancestry) who have been extensively phenotyped for depression and related neurocognitive phenotypes. PGS associations with depression severity and diagnosis were generally modest, and larger in adults than children. Polygenic prediction of depression-related phenotypes was mixed and varied by PGS. Higher PGSBD, in adults, was associated with a higher likelihood of having suicidal ideation, increased brooding and anhedonia, and lower levels of cognitive reappraisal; PGSMDD was positively associated with brooding and negatively related to cognitive reappraisal. Overall, PGS based on both broad and clinical depression phenotypes have modest utility in adult and child samples of depression.

scholarly journals Polygenic scores for UK Biobank scale data

2018 ◽  
Author(s):  
Timothy Shin Heng Mak ◽  
Robert Milan Porsch ◽  
Shing Wan Choi ◽  
Pak Chung Sham
Keyword(s):  
External Source ◽  
Summary Statistics ◽  
Uk Biobank ◽  
Validation Data ◽  
Raw Data ◽  
Cross Prediction ◽  
Polygenic Scores ◽  
The Difference ◽  
The Uk ◽  
Meta Analyses

AbstractPolygenic scores (PGS) are estimated scores representing the genetic tendency of an individual for a disease or trait and have become an indispensible tool in a variety of analyses. Typically they are linear combination of the genotypes of a large number of SNPs, with the weights calculated from an external source, such as summary statistics from large meta-analyses. Recently cohorts with genetic data have become very large, such that it would be a waste if the raw data were not made use of in constructing PGS. Making use of raw data in calculating PGS, however, presents us with problems of overfitting. Here we discuss the essence of overfitting as applied in PGS calculations and highlight the difference between overfitting due to the overlap between the target and the discovery data (OTD), and overfitting due to the overlap between the target the the validation data (OTV). We propose two methods — cross prediction and split validation — to overcome OTD and OTV respectively. Using these two methods, PGS can be calculated using raw data without overfitting. We show that PGSs thus calculated have better predictive power than those using summary statistics alone for six phenotypes in the UK Biobank data.

scholarly journals Machine Learning Prediction of Biomarkers from SNPs and of Disease Risk from Biomarkers in the UK Biobank

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 991
Author(s):  
Erik Widen ◽  
Timothy G. Raben ◽  
Louis Lello ◽  
Stephen D. H. Hsu
Keyword(s):  
Disease Risk ◽  
Smoking Status ◽  
Glycated Haemoglobin ◽  
European Ancestry ◽  
Risk Scores ◽  
Common Disease ◽  
Atherosclerotic Cardiovascular Disease ◽  
Uk Biobank ◽  
Lipoprotein A ◽  
The Uk

We use UK Biobank data to train predictors for 65 blood and urine markers such as HDL, LDL, lipoprotein A, glycated haemoglobin, etc. from SNP genotype. For example, our Polygenic Score (PGS) predictor correlates ∼0.76 with lipoprotein A level, which is highly heritable and an independent risk factor for heart disease. This may be the most accurate genomic prediction of a quantitative trait that has yet been produced (specifically, for European ancestry groups). We also train predictors of common disease risk using blood and urine biomarkers alone (no DNA information); we call these predictors biomarker risk scores, BMRS. Individuals who are at high risk (e.g., odds ratio of >5× population average) can be identified for conditions such as coronary artery disease (AUC∼0.75), diabetes (AUC∼0.95), hypertension, liver and kidney problems, and cancer using biomarkers alone. Our atherosclerotic cardiovascular disease (ASCVD) predictor uses ∼10 biomarkers and performs in UKB evaluation as well as or better than the American College of Cardiology ASCVD Risk Estimator, which uses quite different inputs (age, diagnostic history, BMI, smoking status, statin usage, etc.). We compare polygenic risk scores (risk conditional on genotype: PRS) for common diseases to the risk predictors which result from the concatenation of learned functions BMRS and PGS, i.e., applying the BMRS predictors to the PGS output.

scholarly journals Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort

2021 ◽  
pp. 1-9
Author(s):  
Janice L. Atkins ◽  
Luke C. Pilling ◽  
Christine J. Heales ◽  
Sharon Savage ◽  
Chia-Ling Kuo ◽  
...  
Keyword(s):  
Iron Reduction ◽  
Brain Mri ◽  
European Ancestry ◽  
Uk Biobank ◽  
Brain Iron ◽  
Mri Features ◽  
Incident Dementia ◽  
Hfe Mutations ◽  
The Uk

Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2 * measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2 * measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.

scholarly journals 925Ethnic differences and determinants of vitamin D deficiency in the UK Biobank

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Joshua Sutherland ◽  
Ang Zhou ◽  
Matthew Leach ◽  
Elina Hyppönen
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Asian Population ◽  
European Ancestry ◽  
Uk Biobank ◽  
Mixed Ancestry ◽  
Black African ◽  
Hydroxyvitamin D ◽  
The Uk ◽  
Summer Time

Abstract Background While controversy remains regarding optimal vitamin D status, the public health relevance of true vitamin D deficiency is undisputed. There are few contemporary cross-ethnic studies investigating the prevalence and determinants of very low 25-hydroxyvitamin D [25(OH)D] concentrations. Methods We used data from 440,581 UK Biobank participants, of which 415,903 identified as white European, 7,880 Asian, 7,602 black African, 1,383 Chinese, and 6,473 of mixed ancestry. 25(OH)D concentrations were measured by DiaSorin Liaison XL and deficiency defined as ≤ 25 nmol/L 25(OH)D. Results The prevalence of 25(OH)D deficiency was highest among participants of Asian ancestry (57.2% in winter/spring and 50.8% in summer/autumn; followed by black African [38.47%/30.78%], mixed ancestry [36.53%/22.48%], Chinese [33.12%/20.68%] and white European [17.45%/5.90%], P < 1.0E-300). Participants with higher socioeconomic deprivation were more likely to have 25(OH)D deficiency compared to less deprived (P < 1.0E-300 for all comparisons), with the pattern being more apparent among those of white European ancestry and in summer (Pinteraction<6.4E-5 for both). In fully-adjusted analyses, regular consumption of oily fish was effective in mitigating ≤25 nmol/L 25(OH)D deficiency across all ethnicities, whilst outdoor-summer time was less effective for black Africans than white Europeans (OR: 0.89; 95% CI: 0.70, 1.12 and OR: 0.40; 95% CI: 0.38, 0.42, respectively). Conclusions Vitamin D deficiency remains an issue throughout the UK, particularly in lower socioeconomic areas and the UK Asian population, half of whom have vitamin D deficiency across seasons. Key messages The prevalence of 25(OH)D deficiency in the UK is alarming, with certain ethnic and socioeconomic groups considered particularly vulnerable.

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 Genome-wide Polygenic Scores for Multiple Psychiatric and Common Traits Identify Preadolescent Youth with Risk for Suicide

2021 ◽  
Author(s):  
Yoonjung Yoonie Joo ◽  
Seo-Yoon Moon ◽  
Hee-Hwan Wang ◽  
Hyeonjin Kim ◽  
Eun-Ji Lee ◽  
...  
Keyword(s):  
Machine Learning ◽  
Suicidal Ideation ◽  
Family Environment ◽  
Autism Spectrum ◽  
Cognitive Capacity ◽  
European Ancestry ◽  
Environment Interaction ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Preadolescent Youth

Abstract Importance. Suicide is the second leading cause of death in children worldwide but no available means exist to identify the risk in youth. Objective. To predict the risk of suicide in children and to investigate whether and to what extents genetic factors and a major environmental risk factor, early life stress(ELS), influence youth suicide. Design, Setting and Participants. We analyzed the genotype-phenotype data of 11,869 preadolescent children ages 9- to 10-year-old from the Adolescent Brain and Cognitive Development (ABCD) study. We estimated genome-wide polygenic scores (GPSs) of 25 complex traits to investigate their phenome-wide associations and predictive utility with suicidality (suicidal ideation and attempt) with machine learning approaches. Predictors. GPSs of 25 traits including psychiatric disorders, personality, cognitive capacity, and psychological traits. Parent Child Behavior Checklist to measure ELS in youth and Youth Family Environment Scale to assess family environment. Main outcomes and Measures. Records of suicidal ideation and attempt of the participants were derived from the computerized version of Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). Results. We identified three GPSs associated with youth suicidality in multiethnic (n = 7,206) and European-ancestry (n = 5,749) participants: ADHD (P = 3.48x10− 4; odds ratio = 1.13 in multiethnic participants, P = 5.60x10− 5, OR = 1.25 in European-ancestry participants), general happiness (P = 1.43x10− 3; OR = 0.89 in multiethnic, P = 8.61x10− 4, OR = 0.89 in European) and autism spectrum disorder(ASD) (P = 1.81x10− 3; OR = 1.15 in multiethnic, P = 1.26x10− 3, OR = 1.18 in European). We also found a significant GPS-by-environment interaction between the effects of genetic risk factors for ASD and the level of ELS in increasing the risk for suicidal ideation (P = 1.36x10− 2, OR = 1.12 in multiethnic, P = 1.39x10− 3, OR = 1.19 in European). A machine learning model trained on the same data showed moderately accurate prediction of children with overall suicidal ideation with a test ROC-AUC of 0.727 (0.746 in European), and with suicidal attempts with a test ROC-AUC of 0.641 (0.975 in European) in held-out samples. Conclusions and Relevance. This study provides the first quantitative account of polygenic and environmental factors of suicidality in a large, representative population of preadolescent youth. It thus shows the potential utility of the GPSs in identifying a child with high risk for suicidality for early screening, intervention, and prevention.

scholarly journals Causal Effect of the Triglyceride-Glucose Index and the Joint Exposure of Higher Glucose and Triglyceride With Extensive Cardio-Cerebrovascular Metabolic Outcomes in the UK Biobank: A Mendelian Randomization Study

2021 ◽  
Vol 7 ◽  
Author(s):  
Shucheng Si ◽  
Jiqing Li ◽  
Yunxia Li ◽  
Wenchao Li ◽  
Xiaolu Chen ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect ◽  
Heart Diseases ◽  
Cerebrovascular Diseases ◽  
European Ancestry ◽  
Uk Biobank ◽  
Tyg Index ◽  
Metabolic Outcomes ◽  
Meta Regression ◽  
The Uk

Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.

scholarly journals A framework for research into continental ancestry groups of the UK Biobank

2021 ◽  
Author(s):  
Andrei-Emil Constantinescu ◽  
Ruth E Mitchell ◽  
Jie Zheng ◽  
Caroline J Bull ◽  
Nicholas J Timpson ◽  
...  
Keyword(s):  
Population Structure ◽  
Principal Component ◽  
European Ancestry ◽  
Uk Biobank ◽  
Ancestry Group ◽  
The United Kingdom ◽  
Health And Disease ◽  
Birth Data ◽  
The Uk ◽  
Epidemiology Studies

The UK Biobank is a large prospective cohort, based in the United Kingdom, that has deep phenotypic and genomic data on roughly a half a million individuals. Included in this resource are data on approximately 78,000 individuals with "non-white British ancestry". Whilst most epidemiology studies have focused predominantly on populations of European ancestry, there is an opportunity to contribute to the study of health and disease for a broader segment of the population by making use of the UK Biobank's "non-white British ancestry" samples. Here we present an empirical description of the continental ancestry and population structure among the individuals in this UK Biobank subset. Reference populations from the 1000 Genomes Project for Africa, Europe, East Asia, and South Asia were used to estimate ancestry for each individual. Those with at least 80% ancestry in one of these four continental ancestry groups were taken forward (N=62,484). Principal component and K-means clustering analyses were used to identify and characterize population structure within each ancestry group. Of the approximately 78,000 individuals in the UK Biobank that are of "non-white British" ancestry, 50,685, 6,653, 2,782, and 2,364 individuals were associated to the European, African, South Asian, and East Asian continental ancestry groups, respectively. Each continental ancestry group exhibits prominent population structure that is consistent with self-reported country of birth data and geography. Methods outlined here provide an avenue to leverage UK Biobank's deeply phenotyped data allowing researchers to maximise its potential in the study of health and disease in individuals of non-white British ancestry.

scholarly journals Using the UK Biobank as a global reference of worldwide populations: application to measuring ancestry diversity from GWAS summary statistics

2021 ◽  
Author(s):  
Florian Privé
Keyword(s):  
Genetic Diversity ◽  
Cohort Study ◽  
Summary Statistics ◽  
Uk Biobank ◽  
Reference Groups ◽  
Phenotypic Data ◽  
The United Kingdom ◽  
Four Corners ◽  
The World ◽  
The Uk

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on almost 500,000 individuals from across the United Kingdom. Within this dataset, we carefully define 17 distinct ancestry groups from all four corners of the world. Using allele frequencies derived from these global reference groups, we are now able to effectively measure diversity from summary statistics of any genetic dataset. Measuring genetic diversity is an important problem because increasing genetic diversity is key to making new genetic discoveries, while also being a major source of confounding to be aware of in genetics studies.

Shared genetic influences on depression and menopause symptoms

2021 ◽  
pp. 1-11
Author(s):  
Joeri J. Meijsen ◽  
Hanyang Shen ◽  
Mytilee Vemuri ◽  
Natalie L. Rasgon ◽  
Karestan C. Koenen ◽  
...  
Keyword(s):  
Genetic Correlation ◽  
Hot Flashes ◽  
Medication Use ◽  
European Ancestry ◽  
Genetic Influences ◽  
Uk Biobank ◽  
Genetic Analyses ◽  
Correlation Analyses ◽  
The Uk ◽  
Shared Genetic

Abstract Background Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. Methods The analysis included 232 993 women aged 39–71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. Results GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10−15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10−5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. Conclusions These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.

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