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2.
Nat Commun ; 10(1): 1718, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979869

RESUMO

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.


Assuntos
Hipotálamo/metabolismo , Neurônios/metabolismo , Coativador 1 de Receptor Nuclear/genética , Coativador 1 de Receptor Nuclear/metabolismo , Obesidade/genética , Alelos , Animais , Peso Corporal , Linhagem Celular Tumoral , Cruzamentos Genéticos , Deleção de Genes , Técnicas de Introdução de Genes , Variação Genética , Células HEK293 , Heterozigoto , Homeostase , Humanos , Leptina/metabolismo , Masculino , Potenciais da Membrana , Camundongos , Camundongos Transgênicos , Mutação de Sentido Incorreto , Obesidade/metabolismo , Fenótipo
3.
Cell ; 176(4): 729-742.e18, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30661757

RESUMO

Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.

4.
Am J Clin Nutr ; 108(3): 453-475, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535086

RESUMO

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.


Assuntos
Índice de Massa Corporal , Encurtamento do Telômero/fisiologia , Telômero/ultraestrutura , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Grupos Étnicos , Humanos , Leucócitos/ultraestrutura , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Fatores Sexuais
5.
J Pediatr ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30413312

RESUMO

OBJECTIVE: To test the long-term effect on growth status at 24 months of age in formula-fed infants who were randomized to consume a meat- or dairy-based complementary diet from 5 to 12 months of age. STUDY DESIGN: Observational assessments, including anthropometric, dietary, and blood biomarkers, were conducted at 24 months of age, 1 year after the intervention ended. RESULTS: The retention rate at 24 months of age was 84% for the meat group and 81% for the dairy group. Mean (±SD) protein intakes at 24 months of age were 4.1 ± 1.2 and 4.0 ± 1.1 g/kmeat (n = 27) and dairy (n = 26) groups, respectively, and comparable with the estimates of US population intake. At 24 months of age, weight-for-age z score did not differ significantly between groups and was similar to that at 12 months. Length-for-age z score remained significantly higher in the meat group compared with the dairy group, and the average length was 1.9 cm greater in the meat group. Weight-for-length z score also did not differ significantly between groups. Insulin-like growth factor 1 significantly increased from 12 to 24 months of age in both groups, but insulin-like growth factor-binding protein 3 and blood urea nitrogen did not change significantly from 12 to 24 months of age and were comparable between groups. CONCLUSIONS: The protein source-induced distinctive growth patterns observed during infancy persisted at 24 months of age, suggesting a potential long-term impact of early protein quality on growth trajectories in formula-fed infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02142647.

6.
PLoS Genet ; 14(10): e1007591, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30325923

RESUMO

A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individual studies of complex traits and diseases are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) have the potential to be used as controls in these studies. Fully utilizing these and other existing sequencing resources may increase power and could be especially useful in studies where resources to sequence additional samples are limited. However, to date, these large, publicly available genetic resources remain underutilized, or even misused, in large part due to the lack of statistical methods that can appropriately use this summary level data. Here, we present a new method to incorporate external controls in case-control analysis called ProxECAT (Proxy External Controls Association Test). ProxECAT estimates enrichment of rare variants within a gene region using internally sequenced cases and external controls. We evaluated ProxECAT in simulations and empirical analyses of obesity cases using both low-depth of coverage (7x) whole-genome sequenced controls and ExAC as controls. We find that ProxECAT maintains the expected type I error rate with increased power as the number of external controls increases. With an accompanying R package, ProxECAT enables the use of publicly available allele frequencies as external controls in case-control analysis.

7.
Am J Clin Nutr ; 107(5): 734-742, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29722841

RESUMO

Background: Protein intake from cow milk-based infant formula has been associated with rapid weight gain and increased adiposity, but the effect of protein from complementary foods has not been prospectively evaluated, and the effect of protein from sources other than formula during complementary feeding is not clear. Objective: The aim of this study was to directly compare the effect of protein from 2 common complementary food sources, meat and dairy, on infant growth and weight trajectory. Design: Healthy term, formula-fed infants were recruited from the metro Denver area, matched by sex and race/ethnicity and randomly assigned to a meat or a dairy complementary food group from 5 to 12 mo of age. Total protein intake during this 7-mo intervention was ∼3 g ⋅ kg-1 ⋅ d-1 for both groups. Intakes of infant formula, cereal, fruit, and vegetables were ad libitum. Caregivers also completed 3-d diet records at 5, 10, and 12 mo of age. Anthropometric measures were obtained during monthly home visits, and blood samples were collected at 5 and 12 mo of age. Results: Sixty-four infants completed the intervention (meat: n = 32; dairy: n = 32). The average total protein intake (mean ± SD) increased from 2.01 ± 0.06 g ⋅ kg-1 ⋅ d-1 at 5 mo to 3.35 ±0.12 g ⋅ kg-1 ⋅ d-1 at 12 mo and did not differ between groups. Over time, weight and weight-for-age z score increased by 0.48 ± 0.07. However, there was a significant group-by-time interaction for both length-for-age z score (LAZ) and weight-for-length z score (WLZ). Post hoc analysis showed that LAZ increased in the meat group (+0.33 ± 0.09; P = 0.001 over time) and decreased in the dairy group (-0.30 ± 0.10; P = 0.0002 over time); WLZ significantly increased in the dairy group (0.76 ± 0.21; P = 0.000002 over time) compared with the meat group (0.30 ± 0.17; P = 0.55 over time). Insulin-like growth factor I and insulin-like growth factor-binding protein 3 both increased over time without group differences. Conclusions: Protein source may have an important role in regulating growth. In these formula-fed older infants, meat- and dairy-based complementary foods led to distinct growth patterns, especially for length. This trial was registered at www.clinicaltrials.gov as NCT02142647.

9.
Nat Genet ; 50(5): 766-767, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29549330

RESUMO

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

10.
Nat Genet ; 50(1): 26-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273807

RESUMO

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

11.
Sci Rep ; 7(1): 4394, 2017 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-28663568

RESUMO

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

12.
Nutrients ; 9(7)2017 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-28753958

RESUMO

Iron supplementation may have adverse health effects in infants, probably through manipulation of the gut microbiome. Previous research in low-resource settings have focused primarily on anemic infants. This was a double blind, randomized, controlled trial of home fortification comparing multiple micronutrient powder (MNP) with and without iron. Six-month-old, non- or mildly anemic, predominantly-breastfed Kenyan infants in a rural malaria-endemic area were randomized to consume: (1) MNP containing 12.5 mg iron (MNP+Fe, n = 13); (2) MNP containing no iron (MNP-Fe, n = 13); or (3) Placebo (CONTROL, n = 7), from 6-9 months of age. Fecal microbiota were profiled by high-throughput bacterial 16S rRNA gene sequencing. Markers of inflammation in serum and stool samples were also measured. At baseline, the most abundant phylum was Proteobacteria (37.6% of rRNA sequences). The proteobacterial genus Escherichia was the most abundant genus across all phyla (30.1% of sequences). At the end of the intervention, the relative abundance of Escherichia significantly decreased in MNP-Fe (-16.05 ± 6.9%, p = 0.05) and CONTROL (-19.75 ± 4.5%, p = 0.01), but not in the MNP+Fe group (-6.23 ± 9%, p = 0.41). The second most abundant genus at baseline was Bifidobacterium (17.3%), the relative abundance of which significantly decreased in MNP+Fe (-6.38 ± 2.5%, p = 0.02) and CONTROL (-8.05 ± 1.46%, p = 0.01), but not in MNP-Fe (-4.27 ± 5%, p = 0.4445). Clostridium increased in MNP-Fe only (1.9 ± 0.5%, p = 0.02). No significant differences were observed in inflammation markers, except for IL-8, which decreased in CONTROL. MNP fortification over three months in non- or mildly anemic Kenyan infants can potentially alter the gut microbiome. Consistent with previous research, addition of iron to the MNP may adversely affect the colonization of potential beneficial microbes and attenuate the decrease of potential pathogens.


Assuntos
Anemia Ferropriva/epidemiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Ferro/administração & dosagem , Ferro/sangue , Micronutrientes/administração & dosagem , RNA Ribossômico 16S/isolamento & purificação , Anemia Ferropriva/sangue , Anemia Ferropriva/tratamento farmacológico , Antropometria , Bifidobacterium/efeitos dos fármacos , Bifidobacterium/isolamento & purificação , Biomarcadores/sangue , Clostridium/efeitos dos fármacos , Clostridium/isolamento & purificação , Método Duplo-Cego , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Fezes/química , Fezes/microbiologia , Feminino , Humanos , Lactente , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/epidemiologia , Interleucina-8/sangue , Quênia/epidemiologia , Masculino , Micronutrientes/sangue , Micronutrientes/deficiência , Pós , Proteobactérias/efeitos dos fármacos , Proteobactérias/isolamento & purificação , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
13.
Sci Rep ; 6: 35371, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27824142

RESUMO

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 × 10-8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10-7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.


Assuntos
Fibrilação Atrial/genética , Estudos de Associação Genética , Idoso , Estudos de Coortes , Epistasia Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Análise Multivariada , Proteínas Musculares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Canais de Potássio/genética
14.
Eur J Hum Genet ; 24(10): 1479-87, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27049301

RESUMO

We have whole-exome sequenced 176 individuals from the isolated population of the island of Vis in Croatia in order to describe exonic variation architecture. We found 290 577 single nucleotide variants (SNVs), 65% of which are singletons, low frequency or rare variants. A total of 25 430 (9%) SNVs are novel, previously not catalogued in NHLBI GO Exome Sequencing Project, UK10K-Generation Scotland, 1000Genomes Project, ExAC or NCBI Reference Assembly dbSNP. The majority of these variants (76%) are singletons. Comparable to data obtained from UK10K-Generation Scotland that were sequenced and analysed using the same protocols, we detected an enrichment of potentially damaging variants (non-synonymous and loss-of-function) in the low frequency and common variant categories. On average 115 (range 93-140) genotypes with loss-of-function variants, 23 (15-34) of which were homozygous, were identified per person. The landscape of loss-of-function variants across an exome revealed that variants mainly accumulated in genes on the xenobiotic-related pathways, of which majority coded for enzymes. The frequency of loss-of-function variants was additionally increased in Vis runs of homozygosity regions where variants mainly affected signalling pathways. This work confirms the isolate status of Vis population by means of whole-exome sequence and reveals the pattern of loss-of-function mutations, which resembles the trails of adaptive evolution that were found in other species. By cataloguing the exomic variants and describing the allelic structure of the Vis population, this study will serve as a valuable resource for future genetic studies of human diseases, population genetics and evolution in this population.


Assuntos
Exoma , População/genética , Croácia , Evolução Molecular , Frequência do Gene , Humanos , Ilhas , Mutação , Polimorfismo de Nucleotídeo Único , Isolamento Reprodutivo
15.
BMC Genet ; 17 Suppl 2: 6, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26866487

RESUMO

Empirical studies and evolutionary theory support a role for rare variants in the etiology of complex traits. Given this motivation and increasing affordability of whole-exome and whole-genome sequencing, methods for rare variant association have been an active area of research for the past decade. Here, we provide a survey of the current literature and developments from the Genetics Analysis Workshop 19 (GAW19) Collapsing Rare Variants working group. In particular, we present the generalized linear regression framework and associated score statistic for the 2 major types of methods: burden and variance components methods. We further show that by simply modifying weights within these frameworks we arrive at many of the popular existing methods, for example, the cohort allelic sums test and sequence kernel association test. Meta-analysis techniques are also described. Next, we describe the 6 contributions from the GAW19 Collapsing Rare Variants working group. These included development of new methods, such as a retrospective likelihood for family data, a method using genomic structure to compare cases and controls, a haplotype-based meta-analysis, and a permutation-based method for combining different statistical tests. In addition, one contribution compared a mega-analysis of family-based and population-based data to meta-analysis. Finally, the power of existing family-based methods for binary traits was compared. We conclude with suggestions for open research questions.


Assuntos
Estudos de Associação Genética/métodos , Variação Genética , Genoma Humano , Humanos , Modelos Lineares , Modelos Genéticos , Linhagem
16.
Nature ; 526(7571): 82-90, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26367797

RESUMO

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.


Assuntos
Doença/genética , Variação Genética/genética , Genoma Humano/genética , Saúde , Adiponectina/sangue , Alelos , Estudos de Coortes , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Genética Médica , Genética Populacional , Estudo de Associação Genômica Ampla , Genômica , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Anotação de Sequência Molecular , Receptores de LDL/genética , Padrões de Referência , Análise de Sequência de DNA , Triglicerídeos/sangue , Reino Unido
17.
Eur J Hum Genet ; 22(3): 414-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23838599

RESUMO

Several methods to correct for multiple testing within a gene region have been proposed. These methods are useful for candidate gene studies, and to fine map gene-regions from GWAs. The Bonferroni correction and permutation are common adjustments, but are overly conservative and computationally intensive, respectively. Other options include calculating the effective number of independent single-nucleotide polymorphisms (SNPs) or using theoretical approximations. Here, we compare a theoretical approximation based on extreme tail theory with four methods for calculating the effective number of independent SNPs. We evaluate the type-I error rates of these methods using single SNP association tests over 10 gene regions simulated using 1000 Genomes data. Overall, we find that the effective number of independent SNP method by Gao et al, as well as extreme tail theory produce type-I error rates at the or close to the chosen significance level. The type-I error rates for the other effective number of independent SNP methods vary by gene region characteristics. We find Gao et al and extreme tail theory to be efficient alternatives to more computationally intensive approaches to control for multiple testing in gene regions.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Interpretação Estatística de Dados , Testes Genéticos/métodos , Humanos
18.
Hum Mol Genet ; 23(3): 782-95, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24057673

RESUMO

Genome-wide association studies (GWAS) have uncovered many genetic associations for cardiovascular disease (CVD). However, data are limited regarding causal genetic variants within implicated loci. We sought to identify regulatory variants (cis- and trans-eQTLs) affecting expression levels of 93 genes selected by their proximity to SNPs with significant associations in prior GWAS for CVD traits. Expression levels were measured by qRT-PCR in leukocytes from 1846 Framingham Heart Study participants. An additive genetic model was applied to 2.5 million imputed SNPs for each gene. Approximately 45% of genes (N = 38) harbored at least one cis-eSNP after a regional multiple-test adjustment. Applying a more rigorous significance threshold (P < 5 × 10(-8)), we found the expression level of 10 genes was significantly associated with more than one cis-eSNP. The top cis-eSNPs for 7 of these 10 genes exhibited moderate-to-strong association with ≥ 1 CVD clinical phenotypes. Several eSNPs or proxy SNPs (r(2) = 1) were replicated by other eQTL studies. After adjusting for the lead GWAS SNPs for the 10 genes, expression variances explained by top cis-eSNPs were attenuated markedly for LPL, FADS2 and C6orf184, suggesting a shared genetic basis for the GWAS and expression trait. A significant association between cis-eSNPs, gene expression and lipid levels was discovered for LPL and C6orf184. In conclusion, strong cis-acting variants are localized within nearly half of the GWAS loci studied, with particularly strong evidence for a regulatory role of the top GWAS SNP for expression of LPL, FADS2 and C6orf184.


Assuntos
Aterosclerose/genética , Doenças Cardiovasculares/genética , Polimorfismo de Nucleotídeo Único , Simulação por Computador , Ácidos Graxos Dessaturases/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Leucócitos/fisiologia , Lipídeos/sangue , Lipídeos/genética , Lipase Lipoproteica/genética , Massachusetts , Modelos Genéticos , Pseudogenes/genética , Locos de Características Quantitativas , Reprodutibilidade dos Testes , Fatores de Risco
19.
Neurology ; 79(16): 1708-15, 2012 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-23035064

RESUMO

OBJECTIVE: To evaluate the relationship of striatal involvement in Huntington disease (HD) to involvement in other brain regions, CAG repeat size, onset age, and other factors. METHODS: We examined patterns of neuropathologic involvement in 664 HD brains submitted to the Harvard Brain Tissue Resource Center. Brains with concomitant Alzheimer or Parkinson changes (n = 82), more than 20% missing data (n = 46), incomplete sample submission (n = 12), or CAG repeat less than 36 (n = 1) were excluded, leaving 523 cases. Standardized ratings from 0 (absent) to 4 (severe) of gross and microscopic involvement were performed for 50 regions. Cluster analysis reduced the data to 2 main measures of involvement: striatal and cortical. RESULTS: The clusters were correlated with each other (r = 0.42) and with disease duration (striatal: r = 0.35; cortical: r = 0.31). The striatal cluster was correlated with HD repeat size (r = 0.50). The cortical cluster showed a stronger correlation with decreased brain weight (r = -0.52) than the striatal cluster (r = -0.33). The striatal cluster was correlated with younger death age (r = -0.31) and onset age (r = -0.46) while the cortical cluster was not (r = 0.09, r = -0.04, respectively). CONCLUSIONS: The 2 brain clusters had different relationships to the HD CAG repeat size, onset age, and brain weight, suggesting that neuropathologic involvement does not proceed in a strictly coupled fashion. The pattern and extent of involvement varies substantially from one brain to the next. These results suggest that regional involvement in HD brain is modified by factors which, if identified, may lend insight into novel routes to therapeutics.


Assuntos
Córtex Cerebral/patologia , Doença de Huntington/patologia , Neostriado/patologia , Adulto , Idade de Início , Idoso , Autopsia , Encéfalo/patologia , Cadáver , Núcleo Caudado/patologia , Análise por Conglomerados , Feminino , Gliose/patologia , Humanos , Doença de Huntington/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neurônios/patologia , Tamanho do Órgão , Repetições de Trinucleotídeos
20.
PLoS One ; 7(7): e40925, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22815869

RESUMO

BACKGROUND: Accurately modeling LD in simulations is essential to correctly evaluate new and existing association methods. At present, there has been minimal research comparing the quality of existing gene region simulation methods to produce LD structures similar to an existing gene region. Here we compare the ability of three approaches to accurately simulate the LD within a gene region: HapSim (2005), Hapgen (2009), and a minor extension to simple haplotype resampling. METHODOLOGY/PRINCIPAL FINDINGS: In order to observe the variation and bias for each method, we compare the simulated pairwise LD measures and minor allele frequencies to the original HapMap data in an extensive simulation study. When possible, we also evaluate the effects of changing parameters. HapSim produces samples of haplotypes with lower LD, on average, compared to the original haplotype set while both our resampling method and Hapgen do not introduce this bias. The variation introduced across the replicates by our resampling method is quite small and may not provide enough sampling variability to make a generalizable simulation study. CONCLUSION: We recommend using Hapgen to simulate replicate haplotypes from a gene region. Hapgen produces moderate sampling variation between the replicates while retaining the overall unique LD structure of the gene region.


Assuntos
Biologia Computacional/métodos , Simulação por Computador , Genes/genética , Frequência do Gene/genética , Loci Gênicos/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Taxa de Mutação , Polimorfismo de Nucleotídeo Único/genética , Densidade Demográfica , Recombinação Genética/genética
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