Publications by authors named "Gabriel Cuellar-Partida"

49 Publications

Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

Circulation 2021 Jul 15. Epub 2021 Jul 15.

Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, St Lucia, Australia.

Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0-6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. We used genetic and pharmacological methods to investigate the role of acid sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole organ level. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as well as and models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and post-conditioning therapeutic agents. Analysis of human complex trait genetics indicate that variants in the genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using hiPSC-CMs and murine heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors recapitulates this cardioprotective effect. We used an model of myocardial infarction (MI) and two models of donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as pre- or post-conditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054360DOI Listing
July 2021

Phenome-wide analysis highlights putative causal relationships between self-reported migraine and other complex traits.

J Headache Pain 2021 Jul 8;22(1):66. Epub 2021 Jul 8.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Background: Migraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach.

Methods: We leveraged available summary statistics from genome-wide association studies (GWAS) of 1,504 phenotypes and self-reported migraine and inferred pair-wise causal relationships using the latent causal variable (LCV) method.

Results: We identify 18 potential causal relationships between self-reported migraine and other complex traits. Hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping. We observed that sources of abdominal pain and discomfort might influence a higher risk for migraine. Moreover, occupational and environmental factors such as working with paints, thinner or glues, and being exposed to diesel exhaust were causally associated with higher migraine risk. Psychiatric-related phenotypes, including stressful life events, increased migraine risk. In contrast, ever feeling unenthusiastic / disinterested for a whole week, a phenotype related to the psychological well-being of individuals, was a potential outcome of migraine.

Conclusions: Overall, our results suggest a potential vascular component to migraine, highlighting the role of vasoconstriction and platelet clumping. Stressful life events and occupational variables potentially influence a higher migraine risk. Additionally, a migraine could impact the psychological well-being of individuals. Our findings provide novel testable hypotheses for future studies that may inform the design of new interventions to prevent or reduce migraine risk and recurrence.
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http://dx.doi.org/10.1186/s10194-021-01284-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268337PMC
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

A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects.

Nat Commun 2021 06 14;12(1):3595. Epub 2021 Jun 14.

Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, USA.

Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.
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http://dx.doi.org/10.1038/s41467-021-23873-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203611PMC
June 2021

Phenome-wide screening of GWAS data reveals the complex causal architecture of obesity.

Hum Genet 2021 Aug 31;140(8):1253-1265. Epub 2021 May 31.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Objective: In the present study, we sought to identify causal relationships between obesity and other complex traits and conditions using a data-driven hypothesis-free approach that uses genetic data to infer causal associations.

Methods: We leveraged available summary-based genetic data from genome-wide association studies on 1498 phenotypes and applied the latent causal variable method (LCV) between obesity and all traits.

Results: We identified 110 traits causally associated with obesity. Of those, 109 were causal outcomes of obesity, while only leg pain in calves was a causal determinant of obesity. Causal outcomes of obesity included 26 phenotypes associated with cardiovascular diseases, 22 anthropometric measurements, nine with the musculoskeletal system, nine with behavioural or lifestyle factors including loneliness or isolation, six with respiratory diseases, five with body bioelectric impedances, four with psychiatric phenotypes, four related to the nervous system, four with disabilities or long-standing illness, three with the gastrointestinal system, three with use of analgesics, two with metabolic diseases, one with inflammatory response and one with the neurodevelopmental disorder ADHD, among others. In particular, some causal outcomes of obesity included hypertension, stroke, ever having a period of extreme irritability, low forced vital capacity and forced expiratory volume, diseases of the musculoskeletal system, diabetes, carpal tunnel syndrome, loneliness or isolation, high leukocyte count, and ADHD.

Conclusions: Our results indicate that obesity causally affects a wide range of traits and comorbid diseases, thus providing an overview of the metabolic, physiological, and neuropsychiatric impact of obesity on human health.
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http://dx.doi.org/10.1007/s00439-021-02298-9DOI Listing
August 2021

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness.

Front Psychiatry 2021 12;12:643609. Epub 2021 Apr 12.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study ( = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37-2.54]), recent suicide attempt (OR = 1.88 [1.14-3.09]), higher use of tobacco (OR = 1.05 [1.02-1.09]) and misuse of painkillers (e.g., opioids; OR = 1.31 [1.06-1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68-0.83]), escitalopram (OR = 0.75 [0.67-0.85]) and venlafaxine (OR = 0.78 [0.68-0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30-0.67]), escitalopram (OR = 0.45 [0.27-0.74]) and citalopram (OR = 0.32 [0.15-0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.
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http://dx.doi.org/10.3389/fpsyt.2021.643609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072020PMC
April 2021

Utilising multi-large omics data to elucidate biological mechanisms within multiple sclerosis genetic susceptibility loci.

Mult Scler 2021 Apr 19:13524585211004422. Epub 2021 Apr 19.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

Background: Genome-wide association studies (GWAS) have succeeded in identifying over 200 susceptibility loci for multiple sclerosis (MS). However, the potential functional variants and the mechanisms by which these loci affect MS risk remain largely unexplained.

Objectives: We used summary data-based Mendelian randomisation to prioritise risk genes and infer potential biological mechanisms for MS risk loci.

Methods: The data used consisted of DNA methylation ( = 1980) QTL (mQTL) and gene expression ( = 31,684) QTL (eQTL) derived from whole blood as well as MS GWAS summary statistics (14,802 cases, 26,703 controls). The findings were further evaluated using data derived from independent brain mQTL ( = 1160) and eQTL ( = 1194).

Results: In whole blood, we identified two independent genomic loci (lincRNA: and ) with consistent genome-wide significant pleiotropic associations across different omics layers. In brain tissue, a similar effect for the locus was observed but not for , indicating a potential tissue-specific effect for the locus.

Conclusion: We provide in silico evidence for the putative biological mechanisms by which the identified DNA methylation sites and target genes are functionally relevant to MS development in different tissues. Future research targeting these genes and DNA methylation sites will determine their roles in the pathophysiology of MS.
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http://dx.doi.org/10.1177/13524585211004422DOI Listing
April 2021

Evidence of Genetic Overlap Between Circadian Preference and Brain White Matter Microstructure.

Twin Res Hum Genet 2021 02 5;24(1):1-6. Epub 2021 Mar 5.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Several neuroimaging studies have reported associations between brain white matter microstructure and chronotype. However, it is unclear whether those phenotypic relationships are causal or underlined by genetic factors. In the present study, we use genetic data to examine the genetic overlap and infer causal relationships between chronotype and diffusion tensor imaging (DTI) measures. We identify 29 significant pairwise genetic correlations, of which 13 also show evidence for a causal association. Genetic correlations were identified between chronotype and brain-wide mean, axial and radial diffusivities. When exploring individual tracts, 10 genetic correlations were observed with mean diffusivity, 10 with axial diffusivity, 4 with radial diffusivity and 2 with mode of anisotropy. We found evidence for a possible causal association of eveningness with white matter microstructure measures in individual tracts including the posterior limb and the retrolenticular part of the internal capsule; the genu and splenium of the corpus callosum and the posterior, superior and anterior regions of the corona radiata. Our findings contribute to the understanding of how genes influence circadian preference and brain white matter and provide a new avenue for investigating the role of chronotype in health and disease.
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http://dx.doi.org/10.1017/thg.2021.4DOI Listing
February 2021

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

Assessment and visualization of phenome-wide causal relationships using genetic data: an application to dental caries and periodontitis.

Eur J Hum Genet 2021 Feb 3;29(2):300-308. Epub 2020 Oct 3.

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

Hypothesis-free Mendelian randomization studies provide a way to assess the causal relevance of a trait across the human phenome but can be limited by statistical power, sample overlap or complicated by horizontal pleiotropy. The recently described latent causal variable (LCV) approach provides an alternative method for causal inference which might be useful in hypothesis-free experiments across human phenome. We developed an automated pipeline for phenome-wide tests using the LCV approach including steps to estimate partial genetic causality, filter to a meaningful set of estimates, apply correction for multiple testing and then present the findings in a graphical summary termed causal architecture plot. We apply this pipeline to body mass index (BMI) and lipid traits as exemplars of traits where there is strong prior expectation for causal effects, and to dental caries and periodontitis as exemplars of traits where there is a need for causal inference. The results for lipids and BMI suggest that these traits are best viewed as contributing factors on a multitude of traits and conditions, thus providing additional evidence that supports viewing these traits as targets for interventions to improve health. On the other hand, caries and periodontitis are best viewed as a downstream consequence of other traits and diseases rather than a cause of ill health. The automated pipeline is implemented in the Complex-Traits Genetics Virtual Lab ( https://vl.genoma.io ) and results are available in https://view.genoma.io . We propose causal architecture plots based on phenome-wide partial genetic causality estimates as a new way visualizing the overall causal map of the human phenome.
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http://dx.doi.org/10.1038/s41431-020-00734-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868372PMC
February 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

Inference of causal relationships between sleep-related traits and 1,527 phenotypes using genetic data.

Sleep 2021 01;44(1)

Genetic Epidemiology Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Study Objective: Sleep is essential for both physical and mental health, and there is a growing interest in understanding how different factors shape individual variation in sleep duration, quality and patterns, or confer risk for sleep disorders. The present study aimed to identify novel inferred causal relationships between sleep-related traits and other phenotypes, using a genetics-driven hypothesis-free approach not requiring longitudinal data.

Methods: We used summary-level statistics from genome-wide association studies and the latent causal variable (LCV) method to screen the phenome and infer causal relationships between seven sleep-related traits (insomnia, daytime dozing, easiness of getting up in the morning, snoring, sleep duration, napping, and morningness) and 1,527 other phenotypes.

Results: We identify 84 inferred causal relationships. Among other findings, connective tissue disorders increase insomnia risk and reduce sleep duration; depression-related traits increase insomnia and daytime dozing; insomnia, napping, and snoring are affected by obesity and cardiometabolic traits and diseases; and working with asbestos, thinner, or glues may increase insomnia risk, possibly through an increased risk of respiratory disease or socio-economic related factors.

Conclusion: Overall, our results indicate that changes in sleep variables are predominantly the consequence, rather than the cause, of other underlying phenotypes and diseases. These insights could inform the design of future epidemiological and interventional studies in sleep medicine and research.
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http://dx.doi.org/10.1093/sleep/zsaa154DOI Listing
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

Identification of susceptibility variants to benign childhood epilepsy with centro-temporal spikes (BECTS) in Chinese Han population.

EBioMedicine 2020 Jul 21;57:102840. Epub 2020 Jun 21.

Guy's & St Thomas' NHS Foundation Trust and King's College London, NIHR Biomedical Research Centre, London, England United Kingdom. Electronic address:

Background: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease.

Methods: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS.

Findings: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10
Interpretation: This study shows that BECTS risk is at least partially heritable and due to common genetic variants. Additionally, we demonstrate that BECTS risk is substantially increased by maternal smoking around birth.
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http://dx.doi.org/10.1016/j.ebiom.2020.102840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317238PMC
July 2020

Educational attainment polygenic scores are associated with cortical total surface area and regions important for language and memory.

Neuroimage 2020 05 29;212:116691. Epub 2020 Feb 29.

Department of Genetics & Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.

It is well established that higher cognitive ability is associated with larger brain size. However, individual variation in intelligence exists despite brain size and recent studies have shown that a simple unifactorial view of the neurobiology underpinning cognitive ability is probably unrealistic. Educational attainment (EA) is often used as a proxy for cognitive ability since it is easily measured, resulting in large sample sizes and, consequently, sufficient statistical power to detect small associations. This study investigates the association between three global (total surface area (TSA), intra-cranial volume (ICV) and average cortical thickness) and 34 regional cortical measures with educational attainment using a polygenic scoring (PGS) approach. Analyses were conducted on two independent target samples of young twin adults with neuroimaging data, from Australia (N ​= ​1097) and the USA (N ​= ​723), and found that higher EA-PGS were significantly associated with larger global brain size measures, ICV and TSA (R ​= ​0.006 and 0.016 respectively, p ​< ​0.001) but not average thickness. At the regional level, we identified seven cortical regions-in the frontal and temporal lobes-that showed variation in surface area and average cortical thickness over-and-above the global effect. These regions have been robustly implicated in language, memory, visual recognition and cognitive processing. Additionally, we demonstrate that these identified brain regions partly mediate the association between EA-PGS and cognitive test performance. Altogether, these findings advance our understanding of the neurobiology that underpins educational attainment and cognitive ability, providing focus points for future research.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116691DOI Listing
May 2020

Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank.

Nat Commun 2020 02 14;11(1):817. Epub 2020 Feb 14.

Genetic Epidemiology Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Although snoring is common in the general population, its aetiology has been largely understudied. Here we report a genetic study on snoring (n ~ 408,000; snorers ~ 152,000) using data from the UK Biobank. We identify 42 genome-wide significant loci, with an SNP-based heritability estimate of ~10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism are observed. Gene-based associations identify 173 genes, including DLEU7, MSRB3 and POC5, highlighting genes expressed in the brain, cerebellum, lungs, blood and oesophagus. We use polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n ~ 8000). Mendelian randomization analyses suggest a potential causal relationship between high BMI and snoring. Altogether, our results uncover insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond it being a cardinal symptom of OSA.
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http://dx.doi.org/10.1038/s41467-020-14625-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021827PMC
February 2020

TwinsMX: Uncovering the Basis of Health and Disease in the Mexican Population.

Twin Res Hum Genet 2019 12 14;22(6):611-616. Epub 2020 Jan 14.

Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Querétaro, México.

TwinsMX is a national twin registry in Mexico recently created with institutional support from the Universidad Nacional Autónoma de México. It aims to serve as a platform to advance epidemiological and genetic research in the country and to disentangle the genetic and environmental contributions to health and disease in the admixed Mexican population. Here, we describe our recruitment and data collection strategies and discuss both the progress to date and future directions. More information about the registry is available on our website: https://twinsmxofficial.unam.mx/ (content in Spanish).
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http://dx.doi.org/10.1017/thg.2019.112DOI Listing
December 2019

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

New insight into human sweet taste: a genome-wide association study of the perception and intake of sweet substances.

Am J Clin Nutr 2019 06;109(6):1724-1737

Monell Chemical Senses Center, Philadelphia, PA.

Background: Individual differences in human perception of sweetness are partly due to genetics; however, which genes are associated with the perception and the consumption of sweet substances remains unclear.

Objective: The aim of this study was to verify previous reported associations within genes involved in the peripheral receptor systems (i.e., TAS1R2, TAS1R3, and GNAT3) and reveal novel loci.

Methods: We performed genome-wide association scans (GWASs) of the perceived intensity of 2 sugars (glucose and fructose) and 2 high-potency sweeteners (neohesperidin dihydrochalcone and aspartame) in an Australian adolescent twin sample (n = 1757), and the perceived intensity and sweetness and the liking of sucrose in a US adult twin sample (n = 686). We further performed GWASs of the intake of total sugars (i.e., total grams of all dietary mono- and disaccharides per day) and sweets (i.e., handfuls of candies per day) in the UK Biobank sample (n = ≤174,424 white-British individuals). All participants from the 3 independent samples were of European ancestry.

Results: We found a strong association between the intake of total sugars and the single nucleotide polymorphism rs11642841 within the FTO gene on chromosome 16 (P = 3.8 × 10-8) and many suggestive associations (P < 1.0 × 10-5) for each of the sweet perception and intake phenotypes. We showed genetic evidence for the involvement of the brain in both sweet taste perception and sugar intake. There was limited support for the associations with TAS1R2, TAS1R3, and GNAT3 in all 3 European samples.

Conclusions: Our findings indicate that genes additional to those involved in the peripheral receptor system are also associated with the sweet taste perception and intake of sweet-tasting foods. The functional potency of the genetic variants within TAS1R2, TAS1R3, and GNAT3 may be different between ethnic groups and this warrants further investigations.
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http://dx.doi.org/10.1093/ajcn/nqz043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537940PMC
June 2019

Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans.

Hum Mol Genet 2018 08;27(16):2927-2939

University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother-child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7-10
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http://dx.doi.org/10.1093/hmg/ddy206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077796PMC
August 2018

Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.

Nat Genet 2018 06 28;50(6):834-848. Epub 2018 May 28.

Department of Population Health Sciences, Bristol Medical School, Bristol, UK.

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
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http://dx.doi.org/10.1038/s41588-018-0127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980758PMC
June 2018

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Nat Commun 2018 05 14;9(1):1864. Epub 2018 May 14.

Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
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http://dx.doi.org/10.1038/s41467-018-03646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951816PMC
May 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 01 22;50(1):26-41. Epub 2017 Dec 22.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41588-017-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951PMC
January 2018

Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study.

Int J Epidemiol 2018 04;47(2):450-459

Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

Background: Coffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.

Methods: We used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.

Results: For all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.

Conclusions: We found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.
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http://dx.doi.org/10.1093/ije/dyx236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186013PMC
April 2018

Partitioning Phenotypic Variance Due to Parent-of-Origin Effects Using Genomic Relatedness Matrices.

Behav Genet 2018 01 2;48(1):67-79. Epub 2017 Nov 2.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

We propose a new method, G-REMLadp, to estimate the phenotypic variance explained by parent-of-origin effects (POEs) across the genome. Our method uses restricted maximum likelihood analysis of genome-wide genetic relatedness matrices based on individuals' phased genotypes. Genome-wide SNP data from parent child duos or trios is required to obtain relatedness matrices indexing the parental origin of offspring alleles, as well as offspring phenotype data to partition the trait variation into variance components. To calibrate the power of G-REMLadp to detect non-null POEs when they are present, we provide an analytic approximation derived from Haseman-Elston regression. We also used simulated data to quantify the power and Type I Error rates of G-REMLadp, as well as the sensitivity of its variance component estimates to violations of underlying assumptions. We subsequently applied G-REMLadp to 36 phenotypes in a sample of individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We found that the method does not seem to be inherently biased in estimating variance due to POEs, and that substantial correlation between parental genotypes is necessary to generate biased estimates. Our empirical results, power calculations and simulations indicate that sample sizes over 10000 unrelated parent-offspring duos will be necessary to detect POEs explaining < 10% of the variance with moderate power. We conclude that POEs tagged by our genetic relationship matrices are unlikely to explain large proportions of the phenotypic variance (i.e. > 15%) for the 36 traits that we have examined.
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http://dx.doi.org/10.1007/s10519-017-9880-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752821PMC
January 2018

Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study.

Int J Epidemiol 2017 12;46(6):1882-1890

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia.

Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS.

Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians.

Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.
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http://dx.doi.org/10.1093/ije/dyx068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837568PMC
December 2017
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