Publications by authors named "David M Evans"

240 Publications

Shedding light on the genetics of fetal growth.

Nat Genet 2021 Jul 19. Epub 2021 Jul 19.

Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK.

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http://dx.doi.org/10.1038/s41588-021-00902-2DOI Listing
July 2021

The relationship between adrenocortical candidate gene expression and clinical response to hydrocortisone in patients with septic shock.

Intensive Care Med 2021 Jun 29. Epub 2021 Jun 29.

The George Institute for Global Health, Sydney, Australia.

Purpose: To determine if adrenocortical gene expression is associated with clinical outcomes or response to corticosteroid treatment in septic shock.

Methods: A pre-specified nested cohort study of a randomised controlled trial of hydrocortisone compared to placebo in septic shock. Blood was collected for RNAseq analysis prior to treatment with hydrocortisone or placebo. The expression of adrenocortical candidate genes related to pituitary releasing hormones, mineralocorticoid and glucocorticoid receptors, intracellular glucocorticoid metabolism and transport proteins was measured.

Results: From May 2014 to April 2017, 671 patients were enrolled in the nested cohort study, from which 494 samples were available for analysis. We found no evidence of an association between candidate gene expression levels and either 90-day mortality, 28-day mortality or time to shock reversal. We observed evidence of a significant interaction between expression and treatment group for time to shock reversal in two genes; GLCCI1 (HR 3.81, 95%CI 0.57-25.47 vs. HR 0.64, 95%CI 0.13-3.07 for hydrocortisone and placebo respectively, p for interaction 0.008) and BHSD1 (HR 0.55, 95%CI 0.28-1.09 vs. HR 1.32 95%CI 0.67-2.60, p for interaction 0.01).

Conclusions: In patients with septic shock, there is no association between adrenocortical candidate gene expression and mortality. Patients with higher expression of GLCCI1 who received hydrocortisone achieved shock resolution faster than those receiving placebo; conversely, patients who had higher expression of BHSD1 who received hydrocortisone achieved shock resolution slower than those who received placebo. Variation in gene expression may be a mechanism for heterogeneity of treatment response to corticosteroids in septic shock.
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http://dx.doi.org/10.1007/s00134-021-06464-5DOI Listing
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease.

Nat Commun 2021 05 5;12(1):2444. Epub 2021 May 5.

St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10) and osteoarthritis (P = 1.6 × 10). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
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http://dx.doi.org/10.1038/s41467-021-22517-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100170PMC
May 2021

Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.

J Urol 2021 Apr 27:101097JU0000000000001822. Epub 2021 Apr 27.

Institute for Reproductive and Developmental Biology, Imperial College London, UK.

Purpose: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence.

Materials And Methods: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence to further investigate bladder expression of implicated genes and pathways (50) and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models in METAL (http://www.sph.umich.edu/csg/abecasis/metal/), and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction.

Results: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure () gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 () gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001).

Conclusions: We uncovered 2 new risk loci near the genes endothelin 1 (), associated with urgency incontinence, and macrophage receptor with collagenous structure (), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.
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http://dx.doi.org/10.1097/JU.0000000000001822DOI Listing
April 2021

Introduction to the Special Issue on Statistical Genetic Methods for Human Complex Traits.

Behav Genet 2021 05;51(3):165-169

The Division of Epidemiology, Department of Family Medicine and Population Health, Virginia Commonwealth University, Richmond, USA.

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http://dx.doi.org/10.1007/s10519-021-10057-9DOI Listing
May 2021

Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color.

Sci Adv 2021 Mar 10;7(11). Epub 2021 Mar 10.

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
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http://dx.doi.org/10.1126/sciadv.abd1239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946369PMC
March 2021

The Augmented Classical Twin Design: Incorporating Genome-Wide Identity by Descent Sharing Into Twin Studies in Order to Model Violations of the Equal Environments Assumption.

Behav Genet 2021 05 13;51(3):223-236. Epub 2021 Feb 13.

The University of Queensland Diamantina Institute, The University of Queensland, Level 7, 37 Kent St, Brisbane, Australia.

The Classical Twin Method (CTM) compares the similarity of monozygotic (MZ) twins with that of dizygotic (DZ) twins to make inferences about the relative importance of genes and environment in the etiology of individual differences. The design has been applied to thousands of traits across the biomedical, behavioral and social sciences and is arguably the most widely used natural experiment known to science. The fundamental assumption of the CTM is that trait relevant environmental covariation within MZ pairs is the same as that found within DZ pairs, so that zygosity differences in within-pair variance must be due to genetic factors uncontaminated by the environment. This equal environments assumption (EEA) has been, and still is hotly contested, and has been mentioned as a possible contributing factor to the missing heritability conundrum. In this manuscript, we introduce a new model for testing the EEA, which we call the Augmented Classical Twin Design which uses identity by descent (IBD) sharing between DZ twin pairs to estimate separate environmental variance components for MZ and DZ twin pairs, and provides a test of whether these are equal. We show through simulation that given large samples of DZ twin pairs, the model provides unbiased estimates of variance components and valid tests of the EEA under strong assumptions (e.g. no epistatic variance, IBD sharing in DZ twins estimated accurately etc.) which may not hold in reality. Sample sizes in excess of 50,000 DZ twin pairs with genome-wide genetic data are likely to be required in order to detect substantial violations of the EEA with moderate power. Consequently, we recommend that the Augmented Classical Twin Design only be applied to datasets with very large numbers of DZ twin pairs (> 50,000 DZ twin pairs), and given the strong assumptions relating to the absence of epistatic variance, appropriate caution be exercised regarding interpretation of the results.
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http://dx.doi.org/10.1007/s10519-021-10044-0DOI Listing
May 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 Apr;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Modeling Parent-Specific Genetic Nurture in Families with Missing Parental Genotypes: Application to Birthweight and BMI.

Behav Genet 2021 05 16;51(3):289-300. Epub 2021 Jan 16.

Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.

Disaggregation and estimation of genetic effects from offspring and parents has long been of interest to statistical geneticists. Recently, technical and methodological advances have made the genome-wide and loci-specific estimation of direct offspring and parental genetic nurture effects more possible. However, unbiased estimation using these methods requires datasets where both parents and at least one child have been genotyped, which are relatively scarce. Our group has recently developed a method and accompanying software (IMPISH; Hwang et al. in PLoS Genet 16:e1009154, 2020) which is able to impute missing parental genotypes from observed data on sibships and estimate their effects on an offspring phenotype conditional on the effects of genetic transmission. However, this method is unable to disentangle maternal and paternal effects, which may differ in magnitude and direction. Here, we introduce an extension to the original IMPISH routine which takes advantage of all available nuclear families to impute parent-specific missing genotypes and obtain asymptotically unbiased estimates of genetic effects on offspring phenotypes. We apply this this method to data from related individuals in the UK Biobank, showing concordance with previous estimates of maternal genetic effects on offspring birthweight. We also conduct the first GWAS jointly estimating offspring-, maternal-, and paternal-specific genetic effects on body-mass index.
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http://dx.doi.org/10.1007/s10519-020-10040-wDOI Listing
May 2021

Direct and Indirect Effects of Maternal, Paternal, and Offspring Genotypes: Trio-GCTA.

Behav Genet 2021 03 2;51(2):154-161. Epub 2021 Jan 2.

Department of Psychology, University of Oslo, Forskningsveien 3A, 0373, Oslo, Norway.

Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to three exemplar phenotypes: offspring birth weight, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).
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http://dx.doi.org/10.1007/s10519-020-10036-6DOI Listing
March 2021

Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight.

Int J Epidemiol 2021 03;50(1):179-189

University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia.

Background: Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal.

Methods: We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels.

Results: We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [-0.051 (-0.100, -0.003)].

Conclusions: Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.
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http://dx.doi.org/10.1093/ije/dyaa256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938507PMC
March 2021

A cautionary note on using Mendelian randomization to examine the Barker hypothesis and Developmental Origins of Health and Disease (DOHaD).

J Dev Orig Health Dis 2020 Dec 4:1-6. Epub 2020 Dec 4.

The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

Recent studies have used Mendelian randomization (MR) to investigate the observational association between low birth weight (BW) and increased risk of cardiometabolic outcomes, specifically cardiovascular disease, glycemic traits, and type 2 diabetes (T2D), and inform on the validity of the Barker hypothesis. We used simulations to assess the validity of these previous MR studies, and to determine whether a better formulated model can be used in this context. Genetic and phenotypic data were simulated under a model of no direct causal effect of offspring BW on cardiometabolic outcomes and no effect of maternal genotype on offspring cardiometabolic risk through intrauterine mechanisms; where the observational relationship between BW and cardiometabolic risk was driven entirely by horizontal genetic pleiotropy in the offspring (i.e. offspring genetic variants affecting both BW and cardiometabolic disease simultaneously rather than a mechanism consistent with the Barker hypothesis). We investigated the performance of four commonly used MR analysis methods (weighted allele score MR (WAS-MR), inverse variance weighted MR (IVW-MR), weighted median MR (WM-MR), and MR-Egger) and a new approach, which tests the association between maternal genotypes related to offspring BW and offspring cardiometabolic risk after conditioning on offspring genotype at the same loci. We caution against using traditional MR analyses, which do not take into account the relationship between maternal and offspring genotypes, to assess the validity of the Barker hypothesis, as results are biased in favor of a causal relationship. In contrast, we recommend the aforementioned conditional analysis framework utilizing maternal and offspring genotypes as a valid test of not only the Barker hypothesis, but also to investigate hypotheses relating to the Developmental Origins of Health and Disease more broadly.
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http://dx.doi.org/10.1017/S2040174420001105DOI Listing
December 2020

Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort.

Nat Commun 2020 10 26;11(1):5404. Epub 2020 Oct 26.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.

There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.
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http://dx.doi.org/10.1038/s41467-020-19257-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588432PMC
October 2020

Estimating indirect parental genetic effects on offspring phenotypes using virtual parental genotypes derived from sibling and half sibling pairs.

PLoS Genet 2020 10 26;16(10):e1009154. Epub 2020 Oct 26.

The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Australia.

Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to their children. However, given the relative paucity of large-scale family-based cohorts around the world, it is difficult to demonstrate parental genetic effects on human traits, particularly at individual loci. In this manuscript, we illustrate how parental genetic effects on offspring phenotypes, including late onset conditions, can be estimated at individual loci in principle using large-scale genome-wide association study (GWAS) data, even in the absence of parental genotypes. Our strategy involves creating "virtual" mothers and fathers by estimating the genotypic dosages of parental genotypes using physically genotyped data from relative pairs. We then utilize the expected dosages of the parents, and the actual genotypes of the offspring relative pairs, to perform conditional genetic association analyses to obtain asymptotically unbiased estimates of maternal, paternal and offspring genetic effects. We apply our approach to 19066 sibling pairs from the UK Biobank and show that a polygenic score consisting of imputed parental educational attainment SNP dosages is strongly related to offspring educational attainment even after correcting for offspring genotype at the same loci. We develop a freely available web application that quantifies the power of our approach using closed form asymptotic solutions. We implement our methods in a user-friendly software package IMPISH (IMputing Parental genotypes In Siblings and Half Siblings) which allows users to quickly and efficiently impute parental genotypes across the genome in large genome-wide datasets, and then use these estimated dosages in downstream linear mixed model association analyses. We conclude that imputing parental genotypes from relative pairs may provide a useful adjunct to existing large-scale genetic studies of parents and their offspring.
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http://dx.doi.org/10.1371/journal.pgen.1009154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646364PMC
October 2020

Exploring the genetic relationship between hearing impairment and Alzheimer's disease.

Alzheimers Dement (Amst) 2020 25;12(1):e12108. Epub 2020 Sep 25.

School of Biomedical Science and Institute of Health and Biomedical Innovation, Faculty of Health Queensland University of Technology (QUT) Brisbane Queensland Australia.

Introduction: Hearing loss has been identified as the potentially largest modifiable risk factor for Alzheimer's disease (AD), estimated to account for a similar increase in AD risk as the apolipoprotein E () gene.

Methods: We investigated the genetic relationship between hearing loss and AD, and sought evidence for a causal relationship.

Results: We found a significant genetic overlap between hearing impairment and AD and a polygenic risk score for AD was able to significantly predict hearing loss in an independent cohort. Additionally, regions of the genome involved in inflammation were identified to be shared between hearing difficulty and AD. However, causality tests found no significant evidence of a causal relationship between these traits in either direction.

Discussion: Overall, these results show that the relationship between hearing difficulty and AD may, in part, be due to shared genes and immune response pathways between the traits. However, currently available data do not support a causal relationship.
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http://dx.doi.org/10.1002/dad2.12108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517507PMC
September 2020

The Boulder Workshop Question Box.

Authors:
David M Evans

Behav Genet 2021 05 28;51(3):181-190. Epub 2020 Sep 28.

The University of Queensland Diamantina Institute, The University of Queensland, Level 7, 37 Kent St, Translational Research Institute, Woolloongabba, QLD, 4102, Australia.

The International Statistical Genetics Workshop (commonly referred to as the "Boulder Workshop") has been held annually in Boulder, Colorado almost every year since 1990. A staple feature of each workshop has been the presence of a "question box" (either a physical box or an online virtual one) where workshop participants are given the opportunity of asking questions to the faculty. In this manuscript, we have compiled a list of ten "classic" questions that have appeared in one form or another across multiple workshops and our attempts at answering them.
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http://dx.doi.org/10.1007/s10519-020-10022-yDOI Listing
May 2021

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis.

Twin Res Hum Genet 2020 08 5;23(4):204-213. Epub 2020 Aug 5.

The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia.

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10-10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10-6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10-3; p = 2.29 × 10-3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10-3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.
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http://dx.doi.org/10.1017/thg.2020.60DOI Listing
August 2020

Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

Nat Commun 2020 07 14;11(1):3519. Epub 2020 Jul 14.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, BS8 2BN, Bristol, UK.

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.
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http://dx.doi.org/10.1038/s41467-020-17117-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360778PMC
July 2020

Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study.

PLoS Med 2020 07 2;17(7):e1003152. Epub 2020 Jul 2.

Centre for Clinical Epidemiology, Department of Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.

Background: Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program.

Methods And Findings: A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk.

Conclusions: Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention.
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http://dx.doi.org/10.1371/journal.pmed.1003152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331983PMC
July 2020

RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro.

Nat Commun 2020 06 3;11(1):2797. Epub 2020 Jun 3.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK.

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.
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http://dx.doi.org/10.1038/s41467-020-16592-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271210PMC
June 2020

It's in the Bloody Genes!

Authors:
David M Evans

Twin Res Hum Genet 2020 04 19;23(2):96-97. Epub 2020 May 19.

The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

Blood cell concentrations for most cell types are highly heritable. Data from Nick Martin's twin registry provided much of the data for the early heritability and linkage studies of blood cell related traits and have contributed significantly to more recent genomewide association studies that have successfully identified individual genetic loci.
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http://dx.doi.org/10.1017/thg.2020.31DOI Listing
April 2020

Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.

Am J Respir Crit Care Med 2020 09;202(5):700-707

The George Institute for Global Health, Sydney, New South Wales, Australia.

Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown. To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations. From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand. There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13;  = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32;  = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04;  = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22;  = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27;  = 0.04), but total cortisol, aldosterone, and ascorbic acid were not. In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.
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http://dx.doi.org/10.1164/rccm.202002-0281OCDOI Listing
September 2020

Maternal and paternal effects on offspring internalizing problems: Results from genetic and family-based analyses.

Am J Med Genet B Neuropsychiatr Genet 2020 07 1;183(5):258-267. Epub 2020 May 1.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

It is unclear to what extent parental influences on the development of internalizing problems in offspring are explained by indirect genetic effects, reflected in the environment provided by the parent, in addition to the genes transmitted from parent to child. In this study, these effects were investigated using two innovative methods in a large birth cohort. Using maternal-effects genome complex trait analysis (M-GCTA), the effects of offspring genotype, maternal or paternal genotypes, and their covariance on offspring internalizing problems were estimated in 3,801 mother-father-child genotyped trios. Next, estimated genetic correlations within pedigree data, including 10,688 children, were used to estimate additive genetic effects, maternal and paternal genetic effects, and a shared family effect using linear mixed effects modeling. There were no significant maternal or paternal genetic effects on offspring anxiety or depressive symptoms at age 8, beyond the effects transmitted via the genetic pathway between parents and children. However, indirect maternal genetic effects explained a small, but nonsignificant, proportion of variance in childhood depressive symptoms in both the M-GCTA (~4%) and pedigree (~8%) analyses. Our results suggest that parental effects on offspring internalizing problems are predominantly due to transmitted genetic variants, rather than the indirect effect of parental genes via the environment.
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http://dx.doi.org/10.1002/ajmg.b.32784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317352PMC
July 2020

Commentary: Proxy gene-by-environment Mendelian randomization for assessing causal effects of maternal exposures on offspring outcomes.

Int J Epidemiol 2020 08;49(4):1218-1220

The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Australia.

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http://dx.doi.org/10.1093/ije/dyaa069DOI Listing
August 2020

The Effect of Plasma Lipids and Lipid-Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study.

J Bone Miner Res 2020 07 12;35(7):1224-1235. Epub 2020 Mar 12.

Medical Research Council (MRC) Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.

Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship is explained by a specific effect in response to statin use or by a general effect of lipid lowering. We utilized 400 single-nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) genomewide association study (GWAS) from the UK Biobank and dual-energy X-ray absorptiometry (DXA) BMD at four body sites and fracture GWAS from the GEFOS consortium. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels on BMD and fracture. Univariate MR analyses suggested a causal effect of LDL-C on eBMD (β = -0.06; standard deviation change in eBMD per standard deviation change in LDL-C, 95% confidence interval [CI] = -0.08 to -0.04; p = 4 × 10 ), total body BMD (β = -0.05, 95% CI = -0.08 to -0.01, p = 6 × 10 ) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL-C on eBMD and total body BMD were independent of HDL-C and triglycerides. Sensitivity MR analyses suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on eBMD (β = -0.083; -0.132 to -0.034; p = .001) to those excluding these SNPs (β = -0.063; -0.090 to -0.036; p = 8 × 10 ). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL-C levels. Our results suggest that effects of statins on eBMD and total body BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3989DOI Listing
July 2020

Integrating Family-Based and Mendelian Randomization Designs.

Cold Spring Harb Perspect Med 2021 Mar 1;11(3). Epub 2021 Mar 1.

The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland 4102, Australia.

Most Mendelian randomization (MR) studies published in the literature to date have involved analyses of unrelated, putatively independent sets of individuals. However, estimates obtained from these sorts of studies are subject to a range of biases including dynastic effects, assortative mating, residual population stratification, and horizontal pleiotropy. The inclusion of related individuals in MR studies can help control for and, in some cases, estimate the effect of these biases on causal parameters. In this review, we discuss these biases, how they can affect MR studies, and describe three sorts of family-based study designs that can be used to control for them. We conclude that including family information from related individuals is not only possible given the world's existing twin, birth, and large-scale population-based cohorts, but likely to reap rich rewards in understanding the etiology of complex traits and diseases in the near future.
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http://dx.doi.org/10.1101/cshperspect.a039503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919398PMC
March 2021

Use of Mendelian Randomization to Examine Causal Inference in Osteoporosis.

Front Endocrinol (Lausanne) 2019 21;10:807. Epub 2019 Nov 21.

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Epidemiological studies have identified many risk factors for osteoporosis, however it is unclear whether these observational associations reflect true causal effects, or the effects of latent confounding or reverse causality. Mendelian randomization (MR) enables causal relationships to be evaluated, by examining the relationship between genetic susceptibility to the risk factor in question, and the disease outcome of interest. This has been facilitated by the development of two-sample MR analysis, where the exposure and outcome are measured in different studies, and by exploiting summary result statistics from large well-powered genome-wide association studies that are available for thousands of traits. Though MR has several inherent limitations, the field is rapidly evolving and at least 14 methodological extensions have been developed to overcome these. The present paper aims to discuss some of the limitations in the MR analytical framework, and how this method has been applied to the osteoporosis field, helping to reinforce conclusions about causality, and discovering potential new regulatory pathways, exemplified by our recent MR study of sclerostin.
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http://dx.doi.org/10.3389/fendo.2019.00807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882110PMC
November 2019
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