Shared genetic influences on depression and menopause symptoms

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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Abstract P147: Genome Wide Assessment of Shared Genetic Architecture Between Rheumatoid Arthritis and Cardiovascular Diseases Using the UK Biobank Data

Circulation ◽

10.1161/circ.141.suppl_1.p147 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Yanjun Guo ◽

Wonil Chung ◽

Zhilei Shan ◽

Liming Liang

Keyword(s):

Cardiovascular Diseases ◽

Genetic Correlation ◽

Multiple Testing ◽

Mendelian Randomization ◽

Meta Analysis ◽

Uk Biobank ◽

Increased Risk ◽

The Uk ◽

Cardiovascular Traits ◽

Shared Genetic

Background: Patients with RA have a 2-10 folds increased risk of cardiovascular diseases (CVD) and CVD accounts for almost 50% of the excess mortality in patients with RA when compared with general population, but the mechanisms underlying such associations are largely unknown. Methods: We examined the genetic correlation, causality, and shared genetic variants between RA (Ncase=6,756, Ncontrol=452,476) and CVD (Ncase=44,246, Ncontrol=414,986) using LD Score regression (LDSC), generalized summary-data-based Mendelian Randomization (GSMR), and cross-trait meta-analysis in the UK Biobank Data. Results: In the present study, RA was significantly genetically correlated with MI, angina, CHD, and CVD after correcting for multiple testing (Rg ranges from 0.40 to 0.43, P<0.05/5). Interestingly, when stratified by frequent usage of aspirin and paracetamol, we observed increased genetic correlation between RA and CVD for participants without aspirin usage ( Rg increased to 0.54 [95%CI: 0.54, 0.78] for angina; P value=6.69х10 -6 ), and for participants with usage of paracetamol ( Rg increased to 0.75 [95%CI: 0.20, 1.29] for MI; P value=8.90х10 -3 ). Cross-trait meta-analysis identified 9 independent loci that were shared between RA and at least one of the genetically correlated CVD traits including PTPN22 at chr1p13.2 , BCL2L11 at chr2q13 , and CCR3 at chr3p21.31 ( P single trait <1х10 -3 and P meta <5х10 -8 ) highlighting potential shared etiology between them which include accelerating atherosclerosis and upregulating oxidative stress and vascular permeability. Finally, Mendelian randomization analyses observed inconsistent instrumental effects and were unable to conclude the causality and directionality between RA and CVD. Conclusion: Our results supported positive genetic correlation between RA and multiple cardiovascular traits, and frequent usage of aspirin and paracetamol may modify their associations, but instrumental analyses were unable to conclude the causality and directionality between them.

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Biobank scale pharmacogenomics informs the genetic underpinnings of simvastatin use

10.1101/2020.11.23.20235846 ◽

2020 ◽

Author(s):

Frank R Wendt ◽

Dora Koller ◽

Gita A Pathak ◽

Daniel Jacoby ◽

Edward J Miller ◽

...

Keyword(s):

Linear Models ◽

Association Studies ◽

Absolute Risk ◽

African Ancestry ◽

Medication Use ◽

Density Lipoprotein ◽

Interactive Effects ◽

European Ancestry ◽

Uk Biobank ◽

The Uk

AbstractBackground and PurposeStudying drug metabolizing enzymes, encoded by pharmacogenes (PGx), may inform biological mechanisms underlying the diseases for which a medication is prescribed. Until recently, PGx loci could not be studied at biobank scale. Here we analyze PGx haplotype variation to detect associations with medication use in the UK Biobank.MethodsIn 7,649 unrelated African-ancestry (AFR) and 326,214 unrelated European-ancestry (EUR) participants from the UK Biobank, aged 37-73 at time of recruitment, we associated clinically-relevant PGx haplotypes with 265 (EUR) and 17 (AFR) medication use phenotypes using generalized linear models covaried with sex, age, age2, sex×age, sex×age2, and ten principal components of ancestry. Haplotypes across 50 genes were assigned with Stargazer. Our analyses focused on the association of PGx haplotype dose (quantitative predictor), diplotype (categorical predictor), and rare haplotype burden on medication use.ResultsIn EUR, NAT2 metabolizer phenotype (OR=1.05, 95% CI: 1.03-1.08, p=7.03×10−6) and activity score (OR=1.09, 95% CI: 1.05-1.14, p=2.46×10−6) were associated with simvastatin use. The dose of N-acetyltransferase 2 (NAT2)*1 was associated with simvastatin use relative to NAT2*5 (NAT2*1 OR=1.04, 95% CI=1.03-1.07, p=1.37×10−5) and was robust to effects of low-density lipoprotein cholesterol (LDL-C) concentration (NAT2*1 given LDL-C concentration: OR=1.07, 95% CI=1.05-1.09, p=1.14×10−8) and polygenic risk for LDL-C concentration (NAT2*1 given LDL-C PRS: OR=1.09, 95% CI=1.04-1.14, p=2.26×10−4). Interactive effects between NAT2*1, simvastatin use, and LDL-C concentration (OR: 0.957, 95% CI=0.916-0.998, p=0.045) were replicated in eMERGE PGx cohort (OR: 0.987, 95% CI: 0.976-0.998, p=0.029).Conclusions and relevanceWe used biobank-scale data to uncover and replicate a novel association between NAT2 locus variation (and suggestive evidence with several other genes) and better response to simvastatin (and other statins) therapy. The presence of NAT2*1 versus NAT2*5 may therefore be useful for making clinically informative decisions regarding the potential benefit (e.g., absolute risk reduction) in LDL-C concentration prior to statin treatment.Subject termsgenetics, genetic association studies, cardiovascular disease

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Hierarchical clustering of gene-level association statistics reveals shared and differential genetic architecture among traits in the UK Biobank

10.1101/565903 ◽

2019 ◽

Author(s):

Melissa R. McGuirl ◽

Samuel Pattillo Smith ◽

Björn Sandstede ◽

Sohini Ramachandran

Keyword(s):

Hierarchical Clustering ◽

Genetic Architecture ◽

Branch Length ◽

European Ancestry ◽

Uk Biobank ◽

Genetic Associations ◽

Multiple Traits ◽

Gene Level ◽

The Uk ◽

Shared Genetic

AbstractGenome-wide association (GWA) studies have generally focused on a single phenotype of interest. Emerging biobanks that pair genotype data from thousands of individuals with phenotype data using medical records or surveys enable testing for genetic associations in each phenotype assayed. However, methods for characterizing shared genetic architecture among multiple traits are lagging behind. Here, we present a new method, Ward clustering to identify Internal Node branch length outliers using Gene Scores (WINGS), for characterizing shared and divergent genetic architecture among multiple phenotypes. The objective of WINGS (freely available at https://github.com/ramachandran-lab/PEGASUS-WINGS) is to identify groups of phenotypes, or “clusters”, that share a core set of genes enriched for mutations in cases. We show in simulations that WINGS can reliably detect phenotype clusters across a range of percent shared architecture and number of phenotypes included. We then use the gene-level association test PEGASUS with WINGS to characterize shared genetic architecture among 87 case-control and seven quantitative phenotypes in 349,468 unrelated European-ancestry individuals from the UK Biobank. We identify 10 significant phenotype clusters that contain two to eight phenotypes. One significant cluster of seven immunological phenotypes is driven by seven genes; these genes have each been associated with two or more of those same phenotypes in past publications. WINGS offers a precise and efficient new application of Ward hierarchical clustering to generate hypotheses regarding shared genetic architecture among phenotypes in the biobank era.

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

10.31234/osf.io/pn9vb ◽

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.

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

Genes ◽

10.3390/genes12070991 ◽

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.

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

Journal of Alzheimer s Disease ◽

10.3233/jad-201080 ◽

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.

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Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subtractions

Neurology ◽

10.1212/wnl.0000000000012919 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012919

Author(s):

Yanjun Guo ◽

Iyas Daghlas ◽

Padhraig Gormley ◽

Franco Giulianini ◽

Paul M Ridker ◽

...

Keyword(s):

Genetic Correlation ◽

Genetic Relationships ◽

Meta Analysis ◽

European Ancestry ◽

Health Study ◽

Lipoprotein Subfractions ◽

Genetic Components ◽

The Uk ◽

Summary Data

Background and Objective:To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.Methods:We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women’s Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (Ncase=54,552, Ncontrol=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713).Results:There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 (P=0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (P<0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues.Conclusions:The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics.Classification of Evidence:This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

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

International Journal of Epidemiology ◽

10.1093/ije/dyab168.641 ◽

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903561116 ◽

2019 ◽

Vol 116 (21) ◽

pp. 10430-10434 ◽

Cited By ~ 23

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.

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Significant shared heritability underlies suicide attempt and clinically predicted probability of attempting suicide

Molecular Psychiatry ◽

10.1038/s41380-018-0326-8 ◽

2019 ◽

Vol 25 (10) ◽

pp. 2422-2430 ◽

Cited By ~ 16

Author(s):

Douglas M. Ruderfer ◽

Colin G. Walsh ◽

Matthew W. Aguirre ◽

Yosuke Tanigawa ◽

Jessica D. Ribeiro ◽

...

Keyword(s):

Genetic Variation ◽

Suicide Attempt ◽

Genetic Correlation ◽

Genetic Profile ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Common Genetic Variation ◽

Genetic Studies ◽

Patient Reported ◽

The Uk

Abstract Suicide accounts for nearly 800,000 deaths per year worldwide with rates of both deaths and attempts rising. Family studies have estimated substantial heritability of suicidal behavior; however, collecting the sample sizes necessary for successful genetic studies has remained a challenge. We utilized two different approaches in independent datasets to characterize the contribution of common genetic variation to suicide attempt. The first is a patient reported suicide attempt phenotype asked as part of an online mental health survey taken by a subset of participants (n = 157,366) in the UK Biobank. After quality control, we leveraged a genotyped set of unrelated, white British ancestry participants including 2433 cases and 334,766 controls that included those that did not participate in the survey or were not explicitly asked about attempting suicide. The second leveraged electronic health record (EHR) data from the Vanderbilt University Medical Center (VUMC, 2.8 million patients, 3250 cases) and machine learning to derive probabilities of attempting suicide in 24,546 genotyped patients. We identified significant and comparable heritability estimates of suicide attempt from both the patient reported phenotype in the UK Biobank (h2SNP = 0.035, p = 7.12 × 10−4) and the clinically predicted phenotype from VUMC (h2SNP = 0.046, p = 1.51 × 10−2). A significant genetic overlap was demonstrated between the two measures of suicide attempt in these independent samples through polygenic risk score analysis (t = 4.02, p = 5.75 × 10−5) and genetic correlation (rg = 1.073, SE = 0.36, p = 0.003). Finally, we show significant but incomplete genetic correlation of suicide attempt with insomnia (rg = 0.34–0.81) as well as several psychiatric disorders (rg = 0.26–0.79). This work demonstrates the contribution of common genetic variation to suicide attempt. It points to a genetic underpinning to clinically predicted risk of attempting suicide that is similar to the genetic profile from a patient reported outcome. Lastly, it presents an approach for using EHR data and clinical prediction to generate quantitative measures from binary phenotypes that can improve power for genetic studies.

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