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1.
Int J Epidemiol ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31412118

RESUMO

BACKGROUND: Previous observational studies have suggested that coffee intake may be associated with a reduction in cancer risk. Mendelian randomization (MR) studies can help clarify whether the observed associations are likely to be causal. Here we evaluated whether coffee intake is associated with: (i) overall risk of being diagnosed with/dying from any cancer; and (ii) risk of individual cancers. METHODS: We identified 46 155 cases (of which 6998 were fatal) and 270 342 controls of White British ancestry from the UK Biobank cohort (UKB), based on ICD10 diagnoses. Individuals with benign tumours were excluded. Coffee intake was self-reported and recorded based on cup/day consumption. We conducted both observational and summary data MR analyses. RESULTS: There was no observational association between coffee intake and overall cancer risk [odds ratio (OR) per one cup/day increase = 0.99, 95% confidence interval (CI) 0.98, 1.00] or cancer death (OR = 1.01, 0.99, 1.03); the estimated OR from MR is 1.01 (0.94, 1.08) for overall cancer risk and 1.11 (0.95, 1.31) for cancer death. The relationship between coffee intake and individual cancer risks were consistent with a null effect, with most cancers showing little or no associations with coffee. Meta-analysis of our MR findings with publicly available summary data on various cancers do not support a strong causal relationship between coffee and risk of breast, ovarian, lung or prostate cancer, upon correction for multiple testing. CONCLUSIONS: Taken together, coffee intake is not associated with overall risk of being diagnosed with or dying from cancer in UKB. For individual cancers, our findings were not statistically inconsistent with earlier observational studies, although for these we were unable to rule out a small effect on specific types of cancer.

2.
Invest Ophthalmol Vis Sci ; 60(8): 3142-3149, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323684

RESUMO

Purpose: To determine genetic correlations between common myopia and primary open-angle glaucoma (POAG). Methods: We tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method. Results: We did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup-disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 × 10-3) and a significant association between PRS for myopia and disc area (P = 1.59 × 10-9). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = -0.12, P = 1.8 × 10-3), supporting the findings of the PRS approach. Conclusions: Using two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology.

3.
Hum Mol Genet ; 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174203

RESUMO

BACKGROUND: The keratinocyte cancers (KC) basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. METHODS: We first conducted a series of Genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47,742 cases, 634,413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. RESULTS: We found substantial genetic correlations (generally 0.5-1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. CONCLUSIONS: We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

4.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

5.
Genet Epidemiol ; 43(6): 609-616, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31045282

RESUMO

With the advent of very large scale genome-wide association studies (GWASs), the promise of Mendelian randomization (MR) has begun to be fulfilled. However, whilst GWASs have provided essential information on the single nucleotide polymorphisms (SNPs) associated with modifiable risk factors needed for MR, the availability of large numbers of SNP instruments raises issues of how best to use this information and how to deal with potential problems such as pleiotropy. Here we provide commentary on some of the recent advances in the MR analysis, including an overview of the different genetic architectures that are being uncovered for a variety of modifiable risk factors and how users ought to take that into consideration when designing MR studies.

6.
Am J Ophthalmol ; 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31121135

RESUMO

PURPOSE: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. DESIGN: Cross-sectional study. METHODS: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure (IOP), central corneal thickness (CCT), corneal hysteresis (CH), corneal resistance factor (CRF), cup-disc ratio (CDR), and primary open-angle glaucoma (POAG)). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank and the International Glaucoma Genetics Consortium. We calculated genetic correlation (rg) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT and selected diabetes-related traits based on individual level phenotype data in two Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines (SOLAR). RESULTS: Overall, there was little rg between diabetes- and glaucoma-related traits. Specifically, we found a non-significant negative correlation between T2D and POAG (rg=-0.14; p=0.16). Using SOLAR, the genetic correlations between measured IOP, CCT, FBS, fasting insulin and hemoglobin A1c, were null. In contrast, genetic correlations between IOP and POAG (rg ≥0.45; p≤3.0E-04) and between CDR and POAG were high (rg =0.57; p=2.8E-10). However, genetic correlations between corneal properties (CCT, CRF and CH) and POAG were low (rg range: -0.18 - 0.11) and non-significant (p≥0.07). CONCLUSION: These analyses suggest there is limited genetic correlation between diabetes- and glaucoma-related traits.

7.
Psychol Med ; 49(7): 1218-1226, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30929657

RESUMO

BACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.

8.
Am J Clin Nutr ; 109(6): 1724-1737, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31005972

RESUMO

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.

9.
Cancer Epidemiol Biomarkers Prev ; 28(6): 1015-1023, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948449

RESUMO

BACKGROUND: Observational studies evaluating the link between polyunsaturated fatty acids (PUFA) and cancers have yielded mixed findings. We used Mendelian randomization (MR) to evaluate whether genetic evidence supports a causal role for PUFAs on overall cancer outcomes. METHODS: We identified genetic instruments for six PUFAs from previous literature and evaluated their association with overall cancer risk (46,155 cases, 270,342 controls) and cancer mortality (6,998 deaths, 270,342 controls) among the UK Biobank cohort. We used the inverse variance weighted model to combine SNP estimates, and derived log (OR) estimates per SD change in each PUFA. RESULTS: None of the six PUFAs showed association with overall cancer risk or mortality, with narrow confidence interval (CI) ruling out all but very small effects, for example, arachidonic acid (AA) overall cancer risk (OR, 1.02; 95% CI, 1.00-1.03). Sex-specific analysis revealed no associations except α-linolenic acid for potentially reducing cancer risk in men (OR, 0.92; 95% CI, 0.86-0.98; P = 0.02); however, this was nonsignificant after multiple testing correction. From individual cancers, only colorectal cancer showed evidence for a causal association for higher AA levels (OR, 1.05; 95% CI, 1.03-1.07), with similar results for the other correlated PUFAs. CONCLUSIONS: Our study provides no support for the hypothesis that PUFAs reduce overall cancer risk or mortality. Higher AA levels increased the risk for colorectal cancer. IMPACT: Our well-powered MR study provides robust causal inferences for the PUFAs on overall cancer risk and mortality. Future larger studies are warranted to replicate the individual cancer findings.

10.
Psychol Med ; : 1-15, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30874500

RESUMO

BACKGROUND: Frequency and quantity of alcohol consumption are metrics commonly used to measure alcohol consumption behaviors. Epidemiological studies indicate that these alcohol consumption measures are differentially associated with (mental) health outcomes and socioeconomic status (SES). The current study aims to elucidate to what extent genetic risk factors are shared between frequency and quantity of alcohol consumption, and how these alcohol consumption measures are genetically associated with four broad phenotypic categories: (i) SES; (ii) substance use disorders; (iii) other psychiatric disorders; and (iv) psychological/personality traits. METHODS: Genome-Wide Association analyses were conducted to test genetic associations with alcohol consumption frequency (N = 438 308) and alcohol consumption quantity (N = 307 098 regular alcohol drinkers) within UK Biobank. For the other phenotypes, we used genome-wide association studies summary statistics. Genetic correlations (rg) between the alcohol measures and other phenotypes were estimated using LD score regression. RESULTS: We found a substantial genetic correlation between the frequency and quantity of alcohol consumption (rg = 0.52). Nevertheless, both measures consistently showed opposite genetic correlations with SES traits, and many substance use, psychiatric, and psychological/personality traits. High alcohol consumption frequency was genetically associated with high SES and low risk of substance use disorders and other psychiatric disorders, whereas the opposite applies for high alcohol consumption quantity. CONCLUSIONS: Although the frequency and quantity of alcohol consumption show substantial genetic overlap, they consistently show opposite patterns of genetic associations with SES-related phenotypes. Future studies should carefully consider the potential influence of SES on the shared genetic etiology between alcohol and adverse (mental) health outcomes.

11.
Br J Cancer ; 120(5): 565-570, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30733581

RESUMO

BACKGROUND: Whether body mass index (BMI) is causally associated with the risk of being diagnosed with or dying from any cancer remains unclear. Weight reduction has clinical importance for cancer control only if weight gain causes cancer development or death. We aimed to answer the question 'does genetically predicted BMI influence my risk of being diagnosed with or dying from any cancer'. METHODS: We used a Mendelian randomisation (MR) approach to estimate causal effect of BMI in 46,155 white-British participants aged between 40 and 69 years at recruitment (median age at follow-up 61 years) from the UK Biobank, who developed any type of cancer, among whom 6998 died from cancer. To derive MR instruments for BMI, we selected up to 390,628 cancer-free participants. RESULTS: For each standard deviation (4.78 units) increase in genetically predicted BMI, we estimated a causal odds ratio (COR) of 1.07 (1.02-1.12) and 1.28 (1.16-1.41) for overall cancer risk and mortality, respectively. The corresponding estimates were similar for males and females, and smokers and non-smokers. CONCLUSIONS: Higher genetically predicted BMI increases the risk of being diagnosed with or dying from any cancer. These data suggest that increased overall weight may causally increase overall cancer incidence and mortality among Europeans.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30716477

RESUMO

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.

14.
Hum Mol Genet ; 27(24): 4315-4322, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30508204

RESUMO

There is considerable debate regarding the role that 25-hydroxyvitamin D [25(OH)D] concentrations play in cancer risk or mortality, with earlier studies drawing mixed conclusions. Using data from the UK Biobank (UKB), we evaluate whether genetically predicted 25(OH)D concentrations are associated with overall cancer susceptibility and cancer mortality using five 25(OH)D genetic markers. Data comprised 438 870 white British UKB participants aged 37-73, including 46 155 cancer cases and 6998 cancer-specific deaths. Participants with keratinocyte cancers and/or benign tumors were excluded from the analysis. Odds ratios were calculated per 20 nmol/L increase in genetically predicted 25(OH)D for cancer risk and cancer mortality. For individual cancer risks, estimates were meta-analyzed with publicly available data using a fixed-effect inverse-variance-weighted model. We demonstrated that genetically low plasma 25(OH)D concentrations were not associated with increased cancer risk nor cancer mortality. Stratification by sex or cancer types did not reveal any meaningful differences albeit wider confidence intervals. Fixed-effect meta-analysis of our individual cancer risk estimates with those derived from publicly available cancer consortia data and previous studies further reinforced our null Mendelian randomization findings on prostate, lung, colorectal and breast cancers with tight confidence intervals; for ovarian and pancreatic cancers, our estimates were less precise despite being not statistically significant. Taken altogether, our results provide no genetic evidence for an association between vitamin D and overall cancer outcomes, with tight confidence intervals to exclude all but very small effect sizes.

15.
Nat Commun ; 9(1): 4774, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429480

RESUMO

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

16.
Sci Rep ; 8(1): 16414, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442986

RESUMO

Consumption of coffee, tea and alcohol might be shaped by individual differences in bitter taste perception but inconsistent observational findings provide little insight regarding causality. We conducted Mendelian randomization analyses using genetic variants associated with the perception of bitter substances (rs1726866 for propylthiouracil [PROP], rs10772420 for quinine and rs2597979 for caffeine) to evaluate the intake of coffee, tea and alcohol among up to 438,870 UK Biobank participants. A standard deviation (SD) higher in genetically predicted bitterness of caffeine was associated with increased coffee intake (0.146 [95%CI: 0.103, 0.189] cups/day), whereas a SD higher in those of PROP and quinine was associated with decreased coffee intake (-0.021 [-0.031, -0.011] and -0.081 [-0.108, -0.054] cups/day respectively). Higher caffeine perception was also associated with increased risk of being a heavy (>4 cups/day) coffee drinker (OR 1.207 [1.126, 1.294]). Opposite pattern of associations was observed for tea possibly due to the inverse relationship between both beverages. Alcohol intake was only negatively associated with PROP perception (-0.141 [-1.88, -0.94] times/month per SD increase in PROP bitterness). Our results reveal that bitter perception is causally associated with intake of coffee, tea and alcohol, suggesting a role of bitter taste in the development of bitter beverage consumption.

17.
Genome Res ; 28(11): 1621-1635, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30333196

RESUMO

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4 Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.

18.
JAMA Ophthalmol ; 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30267046

RESUMO

Importance: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. Objectives: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). Design, Setting, and Participants: This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018. Main Outcomes and Measures: The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT. Results: A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%. Conclusions and Relevance: The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

19.
Invest Ophthalmol Vis Sci ; 59(10): 4054-4064, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098192

RESUMO

Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1. Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.

20.
Nat Neurosci ; 21(9): 1161-1170, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

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