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1.
Artigo em Inglês | MEDLINE | ID: mdl-32372567

RESUMO

Autism spectrum disorder (ASD) is a relatively common childhood onset neurodevelopmental disorder with a complex genetic etiology. While progress has been made in identifying the de novo mutational landscape of ASD, the genetic factors that underpin the ASD's tendency to run in families are not well understood. In this study, nine extended pedigrees each with three or more individuals with ASD, and others with a lesser autism phenotype, were phenotyped and genotyped in an attempt to identify heritable copy number variants (CNVs). Although these families have previously generated linkage signals, no rare CNV segregated with these signals in any family. A small number of clinically relevant CNVs were identified. Only one CNV was identified that segregated with ASD phenotype; namely, a duplication overlapping DLGAP2 in three male offspring each with an ASD diagnosis. This gene encodes a synaptic scaffolding protein, part of a group of proteins known to be pathologically implicated in ASD. On the whole, however, the heritable nature of ASD in the families studied remains poorly understood.

2.
Bioinformatics ; 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32449747

RESUMO

MOTIVATION: Research supports the potential use of microbiome as a predictor of some diseases. Motivated by the findings that microbiome data is complex in nature and there is an inherent correlation due to hierarchical taxonomy of microbial Operational Taxonomic Units (OTUs), we propose a novel machine learning method incorporating a stratified approach to group OTUs into phylum clusters. Convolutional Neural Networks (CNNs) were used to train within each of the clusters individually. Further, through an ensemble learning approach, features obtained from each cluster were then concatenated to improve prediction accuracy. Our two-step approach comprising of stratification prior to combining multiple CNNs, aided in capturing the relationships between OTUs sharing a phylum efficiently, as compared to using a single CNN ignoring OTU correlations. RESULTS: We used simulated datasets containing 168 OTUs in 200 cases and 200 controls for model testing. Thirty-two OTUs, potentially associated with risk of disease were randomly selected and interactions between three OTUs were used to introduce non-linearity. We also implemented this novel method in two human microbiome studies: (i) cirrhosis with 118 cases, 114 controls; (ii) type 2 diabetes with 170 cases, 174 controls; to demonstrate the model's effectiveness. Extensive experimentation and comparison against conventional machine learning techniques yielded encouraging results. We obtained mean AUC values of 0.88, 0.92, 0.75, showing a consistent increment (5%, 3%, 7%) in simulations, cirrhosis and type 2 diabetes data respectively, against the next best performing method, Random Forest. AVAILABILITY: https://github.com/divya031090/TaxoNN_OTU.

3.
Clin Epigenetics ; 12(1): 52, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32248841

RESUMO

BACKGROUND: Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath's four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. RESULTS: Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18-20 years after DNAm measurement. However, higher PhenoAge (ß = 0.023, p = 0.007) and GrimAge (ß = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E-3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (ß = 0.38, p = 0.026) and T1D duration (ß = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (ß = - 1.99, p = 0.045) and leisure time (ß = - 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (ß = 0.09, p = 0.048) and current smoking (ß = 7.13, p = 9.03E-50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. CONCLUSIONS: Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

5.
Diabetes ; 69(4): 784-795, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32005708

RESUMO

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with P replication < 0.05 and P combined < P discovery In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of STK39, with an effect size comparable with those of common variants in the INS and PTPN22 loci (combined [from the discovery and replication cohorts] estimate of odds ratio [ORcombined] 1.97, 95% CI 1.58-2.47, P combined = 2.9 × 10-9). Pharmacological inhibition of Stk39 activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.

6.
Acta Diabetol ; 57(2): 237-245, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31473834

RESUMO

AIMS: The incidence of microvascular complications, including diabetic retinopathy (DR), increases with duration of type 2 diabetes (T2D). Meta-GWAS have reported numerous single-nucleotide polymorphisms (SNPs) associated with T2D; however, no loci, achieving genome-wide significance has been reported for DR. Vascular endothelial growth factor A (VEGFA) and insulin-like growth factor 1 (IGF1) are considered as potential genetic candidates involved in T2D and DR progression. Moreover, the association of serum levels of these proteins with diabetes-related traits is controversial. Therefore, the current study was designed to evaluate the possible genetic predisposition and role of these circulating growth factors in serum in the pathophysiology of T2D and DR. METHODS: A cohort of 1126 individuals with T2D was collected including those without retinopathy (DNR = 573), non-progressive diabetic retinopathy (NPDR = 301) and progressive diabetic retinopathy (PDR = 252), and 348 healthy controls. Genomic DNA was isolated, and six SNPs: rs833061, rs13207351, rs1570360, rs2010963, rs5742632 and rs6214, were genotyped and results statistically analyzed. ELISA was performed on a subset of the samples to measure serum levels of IGF1 and VEGFA. RESULTS: The minor allele of rs6214 was associated with T2D [OR = 1.67 (95% CI 1.39-2.01, p = 4.9E-8)], rs13207351 was associated with NPDR [OR = 1.97 (95% CI 1.28-3.03, p = 9.0E-3)]when compared with DNR, and rs5742632 showed positive association with PDR [OR = 1.66 (95% CI 1.33-2.05, p = 1.0E-4)] compared to DNR. Lowered IGF1 serum levels were found to be associated with T2D, NPDR and PDR. CONCLUSIONS: IGF1 was found to increase the T2DM susceptibility as well as advanced DR, i.e., PDR, while VEGFA was found to be associated with early DR stage, i.e., NPDR.

7.
Rheumatology (Oxford) ; 59(1): 90-98, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31236574

RESUMO

OBJECTIVE: LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). METHODS: Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed. RESULTS: Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002). CONCLUSION: We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort.


Assuntos
Idade de Início , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Adolescente , Adulto , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/etnologia , Nefrite Lúpica/etnologia , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
8.
Diabetes ; 68(12): 2235-2246, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31506345

RESUMO

Extreme obesity (EO) (BMI >50 kg/m2) is frequently associated with neuropsychiatric disease (NPD). As both EO and NPD are heritable central nervous system disorders, we assessed the prevalence of protein-truncating variants (PTVs) and copy number variants (CNVs) in genes/regions previously implicated in NPD in adults with EO (n = 149) referred for weight loss/bariatric surgery. We also assessed the prevalence of CNVs in patients referred to University College London Hospital (UCLH) with EO (n = 218) and obesity (O) (BMI 35-50 kg/m2; n = 374) and a Swedish cohort of participants from the community with predominantly O (n = 161). The prevalence of variants was compared with control subjects in the Exome Aggregation Consortium/Genome Aggregation Database. In the discovery cohort (high NPD prevalence: 77%), the cumulative PTV/CNV allele frequency (AF) was 7.7% vs. 2.6% in control subjects (odds ratio [OR] 3.1 [95% CI 2-4.1]; P < 0.0001). In the UCLH EO cohort (intermediate NPD prevalence: 47%), CNV AF (1.8% vs. 0.9% in control subjects; OR 1.95 [95% CI 0.96-3.93]; P = 0.06) was lower than the discovery cohort. CNV AF was not increased in the UCLH O cohort (0.8%). No CNVs were identified in the Swedish cohort with no NPD. These findings suggest that PTV/CNVs, in genes/regions previously associated with NPD, may contribute to NPD in patients with EO.

9.
Kidney Int Rep ; 4(7): 995-1003, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31317121

RESUMO

Introduction: Discordance in kidney disease severity between affected relatives is a recognized feature of autosomal dominant polycystic kidney disease (ADPKD). Here, we report a systematic study of a large cohort of families to define the prevalence and clinical features of intrafamilial discordance in ADPKD. Methods: The extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney disease center. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney volume by magnetic resonance imaging (MRI) was available in 500 study patients. Results: Based on (i) rate of estimated glomerular filtration rate (eGFR) decline, (ii) age at onset of end-stage renal disease (ESRD), and (iii) Mayo Clinic Imaging Classification (MCIC), 20% of patients were classified as having mild disease, and 33% as having severe disease. Intrafamilial ADPKD discordance with at least 1 mild and 1 severe case was observed in 43 of 371 (12%) families, at a similar frequency regardless of the responsible gene (PKD1/PKD2/no mutation detected) or mutation type (protein-truncating versus nontruncating). Intrafamilial discordance was more common in larger families and was present in 30% of families with more than 5 affected members. The heritability of age at onset of ESRD was similar between different mutation types. Conclusion: Extreme kidney disease discordance is present in at least 12% of families with ADPKD, regardless of the underlying mutated gene or mutation class. Delineating genetic and environmental modifiers underlying the observed intrafamilial ADPKD variability will provide novel insights into the mechanisms of progression in ADPKD.

10.
Am J Hum Genet ; 105(1): 78-88, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178127

RESUMO

Relationship estimation and segment detection between individuals is an important aspect of disease gene mapping. Existing methods are either tailored for computational efficiency or require phasing to improve accuracy. We developed TRUFFLE, a method that integrates computational techniques and statistical principles for the identification and visualization of identity-by-descent (IBD) segments using un-phased data. By skipping the haplotype phasing step and, instead, relying on a simpler region-based approach, our method is computationally efficient while maintaining inferential accuracy. In addition, an error model corrects for segment break-ups that occur as a consequence of genotyping errors. TRUFFLE can estimate relatedness for 3.1 million pairs from the 1000 Genomes Project data in a few minutes on a typical laptop computer. Consistent with expectation, we identified only three second cousin or closer pairs across different populations, while commonly used methods identified a large number of such pairs. Similarly, within populations, we identified many fewer related pairs. Compared to methods relying on phased data, TRUFFLE has comparable accuracy but is drastically faster and has fewer broken segments. We also identified specific local genomic regions that are commonly shared within populations, suggesting selection. When applied to pedigree data, we observed 99.6% accuracy in detecting 1st to 5th degree relationships. As genomic datasets become much larger, TRUFFLE can enable disease gene mapping through implicit shared haplotypes by accurate IBD segment detection.

11.
Inflamm Bowel Dis ; 25(11): 1796-1804, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31251335

RESUMO

Excessive intestinal permeability or intestinal barrier dysfunction as measured by various assays has been observed in various diseases. However, little is known about the factors contributing to altered gut permeability in these diseases. Our objective was to determine the genetic determinants of altered gut permeability as measured by the lactulose mannitol fractional excretion ratio (LacMan ratio) in 1075 healthy first-degree relatives of patients with Crohn's disease (CD). In a targeted analysis of single nucleotide polymorphisms (SNPs) located in genes associated with intestinal barrier function related or not to inflammatory bowel disease, we did not find a significant association with intestinal permeability. In an untargeted genome-wide association analysis, the top 100 associations were located in 22 genomic loci, although they were not statistically significant after correction for multiple testing (raw P values [1.8 × 10-7 - 1.4 × 10-5]. The lowest P value was obtained for rs9616637 (22q13.33, C22orf34), for which the minor allele A was associated with a decreased LacMan ratio. These results suggest that host genetic background has limited contribution toward intestinal permeability. Despite this, our study is currently the largest of its kind assessing gut permeability in vivo. It remains possible that smaller genetic effect sizes on LacMan ratio are not detectable in this sized cohort. Larger studies are warranted to identify the potential genetic contribution to intestinal permeability.

12.
Bioinformatics ; 35(21): 4419-4421, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31070701

RESUMO

SUMMARY: For the analysis of high-throughput genomic data produced by next-generation sequencing (NGS) technologies, researchers need to identify linkage disequilibrium (LD) structure in the genome. In this work, we developed an R package gpart which provides clustering algorithms to define LD blocks or analysis units consisting of SNPs. The visualization tool in gpart can display the LD structure and gene positions for up to 20 000 SNPs in one image. The gpart functions facilitate construction of LD blocks and SNP partitions for vast amounts of genome sequencing data within reasonable time and memory limits in personal computing environments. AVAILABILITY AND IMPLEMENTATION: The R package is available at https://bioconductor.org/packages/gpart. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

13.
Diabetes Care ; 42(5): 883-890, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30833370

RESUMO

OBJECTIVE: In type 1 diabetes (T1D), the course of microalbuminuria is unpredictable and timing of glomerular filtration rate (GFR) loss is uncertain. Thus, there is a need to identify the risk factors associated with the development of more advanced stages of kidney disease through large, long-term systematic analysis. RESEARCH DESIGN AND METHODS: Multivariable Cox proportional hazards models assessed the association of baseline and time-dependent glycemic and nonglycemic risk factors for incident macroalbuminuria and reduced estimated GFR (eGFR; defined as <60 mL/min/1.73 m2) over a mean of 27 years in the Diabetes Control and Complications Trial (DCCT) cohort. RESULTS: Higher mean HbA1c (hazard ratio [HR] 1.969 per 1% higher level [95% CI 1.671-2.319]) and male sex (HR 2.767 [95% CI 1.951-3.923]) were the most significant factors independently associated with incident macroalbuminuria, whereas higher mean triglycerides, higher pulse, higher systolic blood pressure (BP), longer diabetes duration, higher current HbA1c, and lower mean weight had lower magnitude associations. For incident reduced eGFR, higher mean HbA1c (HR 1.952 per 1% higher level [95% CI 1.714-2.223]) followed by higher mean triglycerides, older age, and higher systolic BP were the most significant factors. CONCLUSIONS: Although several risk factors associated with macroalbuminuria and reduced eGFR were identified, higher mean glycemic exposure was the strongest determinant of kidney disease among the modifiable risk factors. These findings may inform targeted clinical strategies for the frequency of screening, prevention, and treatment of kidney disease in T1D.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Adolescente , Adulto , Albuminúria/complicações , Glicemia/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/terapia , Nefropatias Diabéticas/tratamento farmacológico , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/epidemiologia , Hiperglicemia/prevenção & controle , Nefropatias/epidemiologia , Nefropatias/etiologia , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Fatores de Risco , Fatores de Tempo , Adulto Jovem
14.
Clin J Am Soc Nephrol ; 14(2): 213-223, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30647093

RESUMO

BACKGROUND AND OBJECTIVES: FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be found in pediatric cases than adults. Consequently, many studies have examined limited gene panels in largely pediatric cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined. RESULTS: The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47±17 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A (A3/A4/A5), 40% were in podocyte genes, and 5% were in CAKUT genes. Many, but not all individuals with COL4A definitely pathogenic variants had some evidence of glomerular basement membrane abnormalities. The estimated mean survival/age of kidney failure for individuals with COL4A definitely pathogenic variants was 58 years (95% confidence interval, 49 to 69), far later than what has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants. CONCLUSIONS: Even with an expanded gene panel, we find that COL4A disorders are the leading monogenic cause in adults diagnosed with FSGS. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_01_15_CJASNPodcast_19_02_.mp3.

15.
Diabetes ; 68(4): 858-867, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30674623

RESUMO

Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 × 10-8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 × 10-8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ≤ 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.


Assuntos
Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla/métodos , Hemoglobina A Glicada/genética , Glicemia/metabolismo , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino
16.
Int J Obes (Lond) ; 43(10): 2057-2065, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30242240

RESUMO

CONTEXT: Adult extreme obesity (EO) is a growing health concern. The prevalence of known obesity associated co-morbidities namely cardio-metabolic and neuro-psychiatric disease in EO is not fully established. The contribution of pathogenic genetic variants, previously implicated in early childhood onset obesity, to adult EO is also not established. OBJECTIVE: We undertook phenotypic and genetic analysis of adult patients with extreme obesity (EO, BMI > 50). Specifically, we assessed the prevalence of eating disorders, cardio-metabolic, and neuro-psychiatric disease and the presence of pathogenic variants in known monogenic obesity genes. DESIGN: A total of 55 patients with EO from a single site bariatric surgery referral program were assessed for the presence of eating disorders, cardio-metabolic, and neuro-psychiatric disease. The 54 obese (O) patients with a BMI < 50 from the same program were identified for phenotypic comparison. The 45 EO patients underwent whole exome sequencing to identify deleterious variants in known monogenic obesity genes. OUTCOMES: (1) Presence of eating disorders, cardio-metabolic, and neuro-psychiatric disease in EO compared to O. (2) Onset of obesity in the EO group. (3) Presence of deleterious variants in genes previously implicated in monogenic obesity in the EO group. RESULTS: The EO group had higher prevalence of lifetime neuro-psychiatric disease (67.3% vs. 37%, p = 0.001) and sleep apnea (74.6% vs. 51.9%, p = 0.01) but lower prevalence of type 2 diabetes (30.1% vs. 50%, p = 0.045) compared to O. There were no significant differences in binge eating, dyslipidemia, hypertension, and cardiac disease. In the EO group, we found previously unreported singleton variants in NTRK2 (pS667W, bio-informatically predicted to be deleterious) and BDNF (pE23K). No previously confirmed loss of function variants in monogenic obesity genes were found. CONCLUSIONS: Adults with EO have significantly increased prevalence of neuro-psychiatric disease and a possibly lower burden of type 2 diabetes compared to less obese patients. Known monogenic causes of obesity were not highly prevalent in this cohort. Further studies are warranted to confirm these preliminary findings.

17.
Diabetologia ; 62(2): 269-280, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30460578

RESUMO

AIMS/HYPOTHESIS: Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4 year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population. METHODS: For this prospective analysis, we included 72,880 participants of the Dutch Lifelines Cohort Study, who underwent baseline investigations between 2007 and 2013, had validated baseline skin autofluorescence values available and were not known to have diabetes or CVD. Individuals were diagnosed with incident type 2 diabetes by self-report or by a fasting blood glucose ≥7.0 mmol/l or HbA1c ≥48 mmol/mol (≥6.5%) at follow-up. Participants were diagnosed as having incident CVD (myocardial infarction, coronary interventions, cerebrovascular accident, transient ischaemic attack, intermittent claudication or vascular surgery) by self-report. Mortality was ascertained using the Municipal Personal Records Database. RESULTS: After a median follow-up of 4 years (range 0.5-10 years), 1056 participants (1.4%) had developed type 2 diabetes, 1258 individuals (1.7%) were diagnosed with CVD, while 928 (1.3%) had died. Baseline skin autofluorescence was elevated in participants with incident type 2 diabetes and/or CVD and in those who had died (all p < 0.001), compared with individuals who survived and remained free of the two diseases. Skin autofluorescence predicted the development of type 2 diabetes, CVD and mortality, independent of several traditional risk factors, such as the metabolic syndrome, glucose and HbA1c. CONCLUSIONS/INTERPRETATION: The non-invasive skin autofluorescence measurement is of clinical value for screening for future risk of type 2 diabetes, CVD and mortality, independent of glycaemic measures and the metabolic syndrome.


Assuntos
Doenças Cardiovasculares/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Imagem Óptica/métodos , Pele/diagnóstico por imagem , Adulto , Idoso , Glicemia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
18.
BMC Proc ; 12(Suppl 9): 32, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275884

RESUMO

Using the real data set from GAW20, we examined changes in the distribution of DNA methylation before and after treatment. Paired analysis of differences in both mean and variance had grossly inflated type 1 error, suggesting either a very large number of changes across the entire epigenome or major non-biological issues, such as batch effects. Separate analysis of Infinium I and II probes indicated differences in the paired t-test statistics between these two types of probes. Examination of combined principal components showed that the first and fourth principal components discriminate between the before and after treatment measurements, further evidencing the presence of batch effects that make any conclusions about treatment effect suspect.

19.
J Am Soc Nephrol ; 29(10): 2593-2600, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30135240

RESUMO

BACKGROUND: Estimating the prevalence of autosomal dominant polycystic kidney disease (ADPKD) is challenging because of age-dependent penetrance and incomplete clinical ascertainment. Early studies estimated the lifetime risk of ADPKD to be about one per 1000 in the general population, whereas recent epidemiologic studies report a point prevalence of three to five cases per 10,000 in the general population. METHODS: To measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime ADPKD prevalence, we used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences). We used stringent criteria for defining rare variants in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5), and potential cystic disease modifiers; evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tools to predict pathogenicity. RESULTS: Identification of high-confidence pathogenic mutations in whole-genome sequencing provided a lower boundary for lifetime ADPKD prevalence of 9.3 cases per 10,000 sequenced. Estimates from whole-genome and exome data were similar. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively. CONCLUSIONS: Population whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD.


Assuntos
Cistos/epidemiologia , Cistos/genética , Hepatopatias/epidemiologia , Hepatopatias/genética , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/genética , Biologia Computacional , Bases de Dados Genéticas , Feminino , Genes Modificadores , Variação Genética , Humanos , Masculino , Mutação , Prevalência , Fatores de Risco , Canais de Cátion TRPP/genética , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
20.
J Neurodev Disord ; 10(1): 20, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29890955

RESUMO

BACKGROUND: Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees. METHODS: ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale. RESULTS: The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent. CONCLUSIONS: Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity.


Assuntos
Transtorno do Espectro Autista/genética , Cromossomos/genética , Ligação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Canadá , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estados Unidos , Adulto Jovem
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