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1.
Biol Psychiatry Glob Open Sci ; 2(2): 115-126, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35712048

RESUMO

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

2.
JCI Insight ; 7(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35446786

RESUMO

Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.


Assuntos
Hipertensão , Insuficiência Renal Crônica , Pressão Sanguínea , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Insuficiência Renal Crônica/genética , Uromodulina/genética
3.
Nat Genet ; 54(4): 437-449, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35361970

RESUMO

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.


Assuntos
Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética
4.
Alzheimers Dement (Amst) ; 14(1): e12280, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35475137

RESUMO

Introduction: The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms. Methods: Genome-wide and epigenome-wide studies (nindividuals ≤1064) were performed on plasma levels of 282 AD-associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter-individual differences in plasma protein levels. Mendelian randomization (MR) and co-localization tested associations between proteins and disease-related phenotypes. Results: Sixty-four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine-phosphate-guanine (CpG) site within the MS4A4A locus. Higher plasma tubulin-specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk. Discussion: Our data inform the regulation of biomarker levels and their relationships with AD.

5.
Biology (Basel) ; 11(3)2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35336768

RESUMO

Thyroid dysfunction appears to be the leading endocrine disorder. We conducted a cross-sectional study on 4402 individuals from three Croatian cohorts. The aim of this study was to analyse the prevalence of diagnosed and undiagnosed hypothyroidism, hyperthyroidism (subclinical and clinical) and positive thyroid antibodies in the Croatian population. The results of the study indicated that 17.6% of participants were euthyroid with positive antibodies. The prevalence of clinical and subclinical hypothyroidism was 3% and 7.4%, respectively, while the prevalence of clinical and subclinical hyperthyroidism was 0.2% and 1.1%, respectively. Among them, 92.6% subclinical hypothyroid, 93.9% clinical hypothyroid, 83% subclinical hyperthyroid and 71.4% clinical hyperthyroid participants were undiagnosed. Finally, the prevalence of undiagnosed subclinical and clinical hypothyroidism in our population was 6.9% and 2.8%, respectively, while the prevalence of undiagnosed subclinical and clinical hyperthyroidism was 0.9% and 0.1%, respectively. Women showed a higher prevalence of thyroid disorders; 1.57 times higher odds of euthyroidism with positive antibodies, 2.1 times higher odds of subclinical hyperthyroidism, 2.37 times higher odds of clinical hypothyroidism and 1.58 times higher odds of subclinical hypothyroidism than men. These results indicate an extremely high proportion of undiagnosed cases, and therefore require investments in a prevention programme.

7.
J Am Soc Nephrol ; 33(3): 511-529, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35228297

RESUMO

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.


Assuntos
Estudo de Associação Genômica Ampla , Rim , Creatinina , Humanos , Polimorfismo de Nucleotídeo Único , Isomerases de Dissulfetos de Proteínas/genética , Uromodulina/genética
8.
Nat Commun ; 13(1): 1586, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35332118

RESUMO

Post-translational modifications diversify protein functions and dynamically coordinate their signalling networks, influencing most aspects of cell physiology. Nevertheless, their genetic regulation or influence on complex traits is not fully understood. Here, we compare the genetic regulation of the same PTM of two proteins - glycosylation of transferrin and immunoglobulin G (IgG). By performing genome-wide association analysis of transferrin glycosylation, we identify 10 significantly associated loci, 9 of which were not reported previously. Comparing these with IgG glycosylation-associated genes, we note protein-specific associations with genes encoding glycosylation enzymes (transferrin - MGAT5, ST3GAL4, B3GAT1; IgG - MGAT3, ST6GAL1), as well as shared associations (FUT6, FUT8). Colocalisation analyses of the latter suggest that different causal variants in the FUT genes regulate fucosylation of the two proteins. Glycosylation of these proteins is thus genetically regulated by both shared and protein-specific mechanisms.


Assuntos
Estudo de Associação Genômica Ampla , Transferrina , Glicosilação , Imunoglobulina G/metabolismo , Processamento de Proteína Pós-Traducional , Transferrina/genética , Transferrina/metabolismo
9.
Chest ; 161(5): 1155-1166, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35104449

RESUMO

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Asma/diagnóstico , Estudo de Associação Genômica Ampla , Humanos , Pulmão , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética
10.
Int J Mol Sci ; 23(4)2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35216288

RESUMO

Thyroglobulin (Tg) is an iodoglycoprotein produced by thyroid follicular cells which acts as an essential substrate for thyroid hormone synthesis. To date, only one genome-wide association study (GWAS) of plasma Tg levels has been performed by our research group. Utilizing recent advancements in computation and modeling, we apply a Bayesian approach to the probabilistic inference of the genetic architecture of Tg. We fitted a Bayesian sparse linear mixed model (BSLMM) and a frequentist linear mixed model (LMM) of 7,289,083 variants in 1096 healthy European-ancestry participants of the Croatian Biobank. Meta-analysis with two independent cohorts (total n = 2109) identified 83 genome-wide significant single nucleotide polymorphisms (SNPs) within the ST6GAL1 gene (p<5×10-8). BSLMM revealed additional association signals on chromosomes 1, 8, 10, and 14. For ST6GAL1 and the newly uncovered genes, we provide physiological and pathophysiological explanations of how their expression could be associated with variations in plasma Tg levels. We found that the SNP-heritability of Tg is 17% and that 52% of this variation is due to a small number of 16 variants that have a major effect on Tg levels. Our results suggest that the genetic architecture of plasma Tg is not polygenic, but influenced by a few genes with major effects.


Assuntos
Estudo de Associação Genômica Ampla , Tireoglobulina , Teorema de Bayes , Estudo de Associação Genômica Ampla/métodos , Genômica , Humanos , Polimorfismo de Nucleotídeo Único , Tireoglobulina/genética
11.
Sci Rep ; 12(1): 574, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022422

RESUMO

High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in-depth multi-omics study of various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP). The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2786 in discovery and n = 1185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (Phewas) were also explored to further investigate these association results. We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the ROC curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist-hip ratio, total fat percentage, body mass index, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, insulin resistance and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach. We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research.


Assuntos
Pressão Sanguínea , Biologia Computacional , Hipertensão/sangue , Fosfolipídeos/sangue , Adulto , Idoso , Biomarcadores/sangue , Fatores de Risco Cardiometabólico , Estudos de Coortes , Diástole , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Sístole
12.
Aging (Albany NY) ; 14(2): 623-659, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35073279

RESUMO

Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to compare fifteen omics ageing clocks, with correlations of 0.21-0.97 with chronAge, even with substantial sub-setting of biomarkers. These clocks track common aspects of ageing with 95% of the variance in chronAge being shared among clocks. The difference between BA and chronAge - omics clock age acceleration (OCAA) - often associates with health measures. One year's OCAA typically has the same effect on risk factors/10-year disease incidence as 0.09/0.25 years of chronAge. Epigenetic and IgG glycomics clocks appeared to track generalised ageing while others capture specific risks. We conclude BA is measurable and prognostic and that future work should prioritise health outcomes over chronAge.


Assuntos
Envelhecimento , Epigênese Genética , Envelhecimento/genética , Relógios Biológicos , Biomarcadores , Metilação de DNA , Epigenômica , Humanos
13.
Elife ; 112022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35023833

RESUMO

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.


Although our genetic code does not change throughout our lives, our genes can be turned on and off as a result of epigenetics. Epigenetics can track how the environment and even certain behaviors add or remove small chemical markers to the DNA that makes up the genome. The type and location of these markers may affect whether genes are active or silent, this is, whether the protein coded for by that gene is being produced or not. One common epigenetic marker is known as DNA methylation. DNA methylation has been linked to the levels of a range of proteins in our cells and the risk people have of developing chronic diseases. Blood samples can be used to determine the epigenetic markers a person has on their genome and to study the abundance of many proteins. Gadd, Hillary, McCartney, Zaghlool et al. studied the relationships between DNA methylation and the abundance of 953 different proteins in blood samples from individuals in the German KORA cohort and the Scottish Lothian Birth Cohort 1936. They then used machine learning to analyze the relationship between epigenetic markers found in people's blood and the abundance of proteins, obtaining epigenetic scores or 'EpiScores' for each protein. They found 109 proteins for which DNA methylation patterns explained between at least 1% and up to 58% of the variation in protein levels. Integrating the 'EpiScores' with 14 years of medical records for more than 9000 individuals from the Generation Scotland study revealed 137 connections between EpiScores for proteins and a future diagnosis of common adverse health outcomes. These included diabetes, stroke, depression, Alzheimer's dementia, various cancers, and inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease. Age-related chronic diseases are a growing issue worldwide and place pressure on healthcare systems. They also severely reduce quality of life for individuals over many years. This work shows how epigenetic scores based on protein levels in the blood could predict a person's risk of several of these diseases. In the case of type 2 diabetes, the EpiScore results replicated previous research linking protein levels in the blood to future diagnosis of diabetes. Protein EpiScores could therefore allow researchers to identify people with the highest risk of disease, making it possible to intervene early and prevent these people from developing chronic conditions as they age.


Assuntos
Doenças Cardiovasculares/diagnóstico , Metilação de DNA/genética , Diabetes Mellitus/diagnóstico , Epigenômica/métodos , Neoplasias/diagnóstico , Proteoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Biomarcadores , Epigênese Genética , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Escócia , Adulto Jovem
14.
Mol Psychiatry ; 27(2): 1111-1119, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34782712

RESUMO

Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from four large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA®). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development (REST), oligodendrocyte maturation (TNFRSF21), and myelination (ARFGEF1). IPA® identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions (MPO, FOXO1, PDE3A, TSLP, NLRP9, ADAMTS5, ROBO1, REST). Furthermore, IPA® identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.

15.
Hepatology ; 75(5): 1081-1094, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34651315

RESUMO

BACKGROUND AND AIMS: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment. APPROACH AND RESULTS: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p < 5 × 10-8 ), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (ANO1) and transmembrane Protein 147 (TMEM147), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C-reactive protein concentrations, and decreased lipoprotein cholesterol concentrations. CONCLUSIONS: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.


Assuntos
Cálculos Biliares , Estudo de Associação Genômica Ampla , Cálculos Biliares/genética , Cálculos Biliares/metabolismo , Motilidade Gastrointestinal , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo Único
16.
Hepatol Commun ; 6(2): 297-308, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34535985

RESUMO

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.


Assuntos
Predisposição Genética para Doença , Hepatopatia Gordurosa não Alcoólica/genética , Aciltransferases/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Apolipoproteínas E/genética , Estudos de Casos e Controles , Códon sem Sentido , Registros Eletrônicos de Saúde , Feminino , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fragmentos de Peptídeos/genética , Fosfolipases A2 Independentes de Cálcio/genética , /genética
17.
JAMA Netw Open ; 4(12): e2136560, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34854908

RESUMO

Importance: Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP. Objective: To identify genetic variants associated with NP susceptibility. Design, Setting, and Participants: This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019. Exposures: Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants. Main Outcomes and Measures: GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication. Results: This study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated. Conclusions and Relevance: To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.


Assuntos
Cromossomos Humanos Par 12/genética , Predisposição Genética para Doença/genética , Neuralgia/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Loci Gênicos/genética , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reino Unido , /genética
18.
EBioMedicine ; 74: 103730, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34883445

RESUMO

BACKGROUND: parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist. METHODS: in order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as 'predicted mRNA expression levels' of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315). FINDINGS: a set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, 'lifetime smoking status' and 'predicted mRNA expression levels' of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. INTERPRETATION: the modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases. FUNDING: NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH.


Assuntos
Metilação de DNA , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Epigenômica/métodos , Histona Desmetilases/genética , Sirtuína 1/genética , Ilhas de CpG , Regulação da Expressão Gênica , Impressão Genômica , Humanos , Estilo de Vida , Fenótipo , Locos de Características Quantitativas
19.
Nutrients ; 13(11)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34836057

RESUMO

The Mediterranean diet (MD) is one of the most healthful dietary patterns, beneficial for humans and the environment. However, the MD has recently exhibited a declining trend, especially in younger and less affluent people. This study investigated the association between socioeconomic indicators and adherence to the MD in 4671 adult subjects from Dalmatia, Croatia (age range 18-98 years; 61.9% were women). Additionally, in the follow-up we examined the change in adherence to the MD and in BMI (subsample, N = 1342; 62.5% were women; mean follow-up time of 5.8 years). The adherence to the MD was based on the Mediterranean Diet Serving Score (range 0-24 points, cut-off value ≥ 14 points), with a prevalence in the overall sample of 28.5%. Higher odds of adherence to the MD were recorded in women, older subjects, and those with higher level of objective material status, while it was less likely in the period after economic crisis of 2007-2008. Additionally, we detected no change in adherence to the MD in the follow-up subsample (-8.5%, p = 0.056), but there was an increase in BMI (+6.5%, p < 0.001). We recorded an increase in adherence for nuts (+127.5%), sweets (+112.6%), red meat (+56.4%), and wine (+50.0%), unlike the reduction in adherence for vegetables (-35.1%), fish (-23.4%), white meat (-11.6%), cereals (-10.9%), and dairy products (-9.6%). Similar results were obtained across all quartiles of objective material status. Over time, the absolute change in the MD score was positively associated with female gender, age, higher education, and moderate physical activity, but it was negatively associated with adherence to the MD at baseline. BMI change was positively associated with female gender, and negatively with initial BMI, initial adherence to the MD, and MD change. Our findings point towards a less than ideal adherence to the MD in the general population of southern Croatia, and identify important characteristics associated with adherence change over time, informing necessary interventions aimed at increasing MD uptake.


Assuntos
Índice de Massa Corporal , Dieta Mediterrânea/estatística & dados numéricos , Comportamento Alimentar/psicologia , Fidelidade a Diretrizes/estatística & dados numéricos , Classe Social , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Croácia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Política Nutricional , Adulto Jovem
20.
Hum Mol Genet ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34791244

RESUMO

Changes in the N-glycosylation of immunoglobulin G (IgG) are often observed in pathological states, such as autoimmune, inflammatory, neurodegenerative, cardiovascular diseases and some types of cancer. However, in most cases it is not clear if the disease onset causes these changes, or if the changes in IgG N-glycosylation are among the risk factors for the diseases. The aim of this study was to investigate the casual relationships between IgG N-glycosylation traits and 12 diseases, in which the alterations of IgG N-glycome were previously reported, using Two Sample Mendelian Randomization (MR) approach. We have performed Two Sample MR using publicly available summary statistics of genome-wide association studies of IgG N-glycosylation and disease risks. Our results indicate positive causal effect of systemic lupus erythematosus (SLE) on the abundance of N-glycans with bisecting N-acetylglucosamine in the total IgG N-glycome. Therefore, we suggest regarding this IgG glycosylation trait as a biomarker of SLE. We also emphasize the need for more powerful GWAS studies of IgG N-glycosylation to further elucidate the causal effect of IgG N-glycome on the diseases.

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