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1.
Nat Commun ; 10(1): 1585, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952852

RESUMO

Sleep is an essential human function but its regulation is poorly understood. Using accelerometer data from 85,670 UK Biobank participants, we perform a genome-wide association study of 8 derived sleep traits representing sleep quality, quantity and timing, and validate our findings in 5,819 individuals. We identify 47 genetic associations at P < 5 × 10-8, of which 20 reach a stricter threshold of P < 8 × 10-10. These include 26 novel associations with measures of sleep quality and 10 with nocturnal sleep duration. The majority of identified variants associate with a single sleep trait, except for variants previously associated with restless legs syndrome. For sleep duration we identify a missense variant (p.Tyr727Cys) in PDE11A as the likely causal variant. As a group, sleep quality loci are enriched for serotonin processing genes. Although accelerometer-derived measures of sleep are imperfect and may be affected by restless legs syndrome, these findings provide new biological insights into sleep compared to previous efforts based on self-report sleep measures.


Assuntos
Polissonografia/métodos , Transtornos do Sono-Vigília/genética , Sono/genética , Acelerometria/métodos , Ritmo Circadiano , Humanos , Polimorfismo de Nucleotídeo Único , Serotonina/genética , Serotonina/metabolismo , Transtornos do Sono-Vigília/diagnóstico , Relação Cintura-Quadril
2.
Nat Commun ; 10(1): 343, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696823

RESUMO

Being a morning person is a behavioural indicator of a person's underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.


Assuntos
Ritmo Circadiano , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , AMP Cíclico/metabolismo , Feminino , Loci Gênicos , Ácido Glutâmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Sono , Reino Unido
3.
Hum Mol Genet ; 28(8): 1392-1401, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30649302

RESUMO

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.


Assuntos
Hormônio Antimülleriano/genética , Pré-Menopausa/fisiologia , Adulto , Fatores Etários , Hormônio Antimülleriano/sangue , Hormônio Antimülleriano/fisiologia , Sequência de Bases , Feminino , Expressão Gênica , Regulação da Expressão Gênica/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Longevidade , Menarca/genética , Pessoa de Meia-Idade , Mitocôndrias/genética , Folículo Ovariano , Ovário , Polimorfismo de Nucleotídeo Único/genética , Pré-Menopausa/genética , Reprodução/genética , Análise de Sequência de DNA , Transcriptoma/genética
4.
Am J Hum Genet ; 104(1): 157-163, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30583798

RESUMO

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10-14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.

6.
Int J Epidemiol ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30423117

RESUMO

Background: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. Methods: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. Results: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. Conclusions: Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

7.
Diabetes ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30352878

RESUMO

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such "favourable adiposity" alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined magnetic resonance imaging (MRI) data with genome-wide association studies (GWAS) of body fat % and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity, but a favourable metabolic profile. Consistent with previous studies, individuals carrying more "favourable adiposity" alleles had higher body fat % and higher BMI, but lower risk of type 2 diabetes, heart disease and hypertension. These individuals also had higher subcutaneous fat, but lower liver fat and lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14 and IRS1, whilst the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified "favourable adiposity" alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglyceride in metabolically low risk depots.

8.
Genet Med ; 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30181606

RESUMO

PURPOSE: Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the penetrance has been overestimated. METHODS: We characterized the prevalence and phenotypic consequences of X chromosome aneuploidy in a population of 244,848 women over 40 years of age from UK Biobank, using single-nucleotide polymorphism (SNP) array data. RESULTS: We detected 30 women with 45,X; 186 with mosaic 45,X/46,XX; and 110 with 47,XXX. The prevalence of nonmosaic 45,X (12/100,000) and 47,XXX (45/100,000) was lower than expected, but was higher for mosaic 45,X/46,XX (76/100,000). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognized Turner syndrome phenotype, including short stature and primary amenorrhea. In contrast, women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. The phenotype of women with 47,XXX included taller stature (5.3 cm; SD = 5.52 cm; P = 5.8 × 10-20) and earlier menopause age (5.12 years; SD = 5.1 years; P = 1.2 × 10-14). CONCLUSION: Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.

9.
Cell Rep ; 23(2): 327-336, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29641994

RESUMO

Fibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed, but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21's mechanisms and therapeutic potential.

10.
Hum Mol Genet ; 27(4): 742-756, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29309628

RESUMO

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

11.
Nat Commun ; 8(1): 744, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963451

RESUMO

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.


Assuntos
Estatura/genética , Peso Corporal/genética , Grupo com Ancestrais do Continente Europeu/genética , Antropometria , Índice de Massa Corporal , Tamanho Corporal/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Relação Cintura-Quadril
12.
PLoS One ; 12(9): e0185083, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28957414

RESUMO

INTRODUCTION: Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. RESULTS: A large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%). RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimer's disease, longevity, age at menopause, bone density, myositis, Parkinson's disease, and age-related macular degeneration. Exclusion of anemic participants did not affect the overall findings. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA, and apoptosis. The majority of RDW-associated signals were intronic (119 of 194), including SNP rs6602909 located in an intron of oncogene GAS6, an eQTL in whole blood. CONCLUSIONS: Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks, and a RDW genetic score was not predictive of incident disease. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.


Assuntos
Envelhecimento/sangue , Envelhecimento/genética , Índices de Eritrócitos/genética , Transdução de Sinais/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Feminino , Ontologia Genética , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido
13.
Nat Genet ; 49(6): 834-841, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28436984

RESUMO

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Menarca/genética , Neoplasias/genética , Puberdade/genética , Ribonucleoproteínas/genética , Adolescente , Fatores Etários , Índice de Massa Corporal , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Impressão Genômica , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco
14.
Hum Mol Genet ; 26(5): 1018-1030, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28040731

RESUMO

As genetic association studies increase in size to 100 000s of individuals, subtle biases may influence conclusions. One possible bias is 'index event bias' (IEB) that appears due to the stratification by, or enrichment for, disease status when testing associations between genetic variants and a disease-associated trait. We aimed to test the extent to which IEB influences some known trait associations in a range of study designs and provide a statistical framework for assessing future associations. Analyzing data from 113 203 non-diabetic UK Biobank participants, we observed three (near TCF7L2, CDKN2AB and CDKAL1) overestimated (body mass index (BMI) decreasing) and one (near MTNR1B) underestimated (BMI increasing) associations among 11 type 2 diabetes risk alleles (at P < 0.05). IEB became even stronger when we tested a type 2 diabetes genetic risk score composed of these 11 variants (-0.010 standard deviations BMI per allele, P = 5 × 10- 4), which was confirmed in four additional independent studies. Similar results emerged when examining the effect of blood pressure increasing alleles on BMI in normotensive UK Biobank samples. Furthermore, we demonstrated that, under realistic scenarios, common disease alleles would become associated at P < 5 × 10- 8 with disease-related traits through IEB alone, if disease prevalence in the sample differs appreciably from the background population prevalence. For example, some hypertension and type 2 diabetes alleles will be associated with BMI in sample sizes of >500 000 if the prevalence of those diseases differs by >10% from the background population. In conclusion, IEB may result in false positive or negative genetic associations in very large studies stratified or strongly enriched for/against disease cases.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Hipertensão/genética , Alelos , Glicemia/genética , Índice de Massa Corporal , Genótipo , Humanos , Hipertensão/patologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único
15.
Int J Epidemiol ; 46(2): 559-575, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28073954

RESUMO

Background: Previous studies have suggested that modern obesogenic environments accentuate the genetic risk of obesity. However, these studies have proven controversial as to which, if any, measures of the environment accentuate genetic susceptibility to high body mass index (BMI). Methods: We used up to 120 000 adults from the UK Biobank study to test the hypothesis that high-risk obesogenic environments and behaviours accentuate genetic susceptibility to obesity. We used BMI as the outcome and a 69-variant genetic risk score (GRS) for obesity and 12 measures of the obesogenic environment as exposures. These measures included Townsend deprivation index (TDI) as a measure of socio-economic position, TV watching, a 'Westernized' diet and physical activity. We performed several negative control tests, including randomly selecting groups of different average BMIs, using a simulated environment and including sun-protection use as an environment. Results: We found gene-environment interactions with TDI (Pinteraction = 3 × 10 -10 ), self-reported TV watching (Pinteraction = 7 × 10 -5 ) and self-reported physical activity (Pinteraction = 5 × 10 -6 ). Within the group of 50% living in the most relatively deprived situations, carrying 10 additional BMI-raising alleles was associated with approximately 3.8 kg extra weight in someone 1.73 m tall. In contrast, within the group of 50% living in the least deprivation, carrying 10 additional BMI-raising alleles was associated with approximately 2.9 kg extra weight. The interactions were weaker, but present, with the negative controls, including sun-protection use, indicating that residual confounding is likely. Conclusions: Our findings suggest that the obesogenic environment accentuates the risk of obesity in genetically susceptible adults. Of the factors we tested, relative social deprivation best captures the aspects of the obesogenic environment responsible.


Assuntos
Índice de Massa Corporal , Dieta , Exercício , Interação Gene-Ambiente , Obesidade/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Meio Ambiente , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco , Comportamento Sedentário , Reino Unido
16.
Nature ; 538(7624): 248-252, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27680694

RESUMO

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.


Assuntos
Envelhecimento/genética , Peso ao Nascer/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feto/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Antropometria , Pressão Sanguínea/genética , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Loci Gênicos/genética , Variação Genética/genética , Impressão Genômica/genética , Genótipo , Glucose/metabolismo , Glicogênio/biossíntese , Humanos , Insulina/metabolismo , Masculino , Fenótipo , Transdução de Sinais
17.
Hum Reprod ; 31(10): 2396-403, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27614355

RESUMO

STUDY QUESTION: Is the length of FMR1 repeat alleles within the normal range associated with the risk of early menopause? SUMMARY ANSWER: The length of repeat alleles within the normal range does not substantially affect risk of early menopause. WHAT IS KNOWN ALREADY: There is a strong, well-established relationship between length of premutation FMR1 alleles and age at menopause, suggesting that this relationship could continue into the normal range. Within the normal range, there is conflicting evidence; differences in ovarian reserve have been identified with FMR1 repeat allele length, but a recent population-based study did not find any association with age at menopause as a quantitative trait. STUDY DESIGN, SIZE, DURATION: We analysed cross-sectional baseline survey data collected at recruitment from 2004 to 2010 from a population-based, prospective epidemiological cohort study of >110 000 women to investigate whether repeat allele length was associated with early menopause. PARTICIPANTS/MATERIALS, SETTING, METHOD: We included 4333 women from the Breakthrough Generations Study (BGS), of whom 2118 were early menopause cases (menopause under 46 years) and 2215 were controls. We analysed the relationship between length of FMR1 alleles and early menopause using logistic regression with allele length as continuous and categorical variables. We also conducted analyses with the outcome age at menopause as a quantitative trait as well as appropriate sensitivity and exploratory analyses. MAIN RESULTS AND THE ROLE OF CHANCE: There was no association of the shorter or longer FMR1 allele or their combined genotype with the clinically relevant end point of early menopause in our main analysis. Likewise, there were no associations with age at menopause as a quantitative trait in our secondary analysis. LIMITATIONS, REASONS FOR CAUTION: Women with homozygous alleles in the normal range may have undetected FMR1 premutation alleles, although there was no evidence to suggest this. We estimate minor dilution of risk of early menopause from the likely inclusion of some women with menopause at over 45 years in the early menopause cases due to age-rounding bias in self-reports. WIDER IMPLICATIONS OF THE FINDINGS: There is no robust evidence in this large study that variation within the normal range of FMR1 repeat alleles influences timing of menopause in the general population, which contradicts findings from some earlier, mainly smaller studies. The FMR1 CGG repeat polymorphism in the normal range is unlikely to contribute to genetic susceptibility to early menopause. STUDY FUNDING/COMPETING INTERESTS: We thank Breast Cancer Now and The Institute of Cancer Research for funding the BGS. The Institute of Cancer Research acknowledges NHS funding to the NIHR Biomedical Research Centre. The study was funded by the Wellcome Trust (grant number 085943). There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Predisposição Genética para Doença , Menopausa Precoce/genética , Menopausa/genética , Repetições de Trinucleotídeos , Adulto , Alelos , Estudos Transversais , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Pessoa de Meia-Idade
18.
PLoS Genet ; 12(8): e1006125, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27494321

RESUMO

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.


Assuntos
Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2/genética , Fator de Transcrição PAX8/genética , Proteínas Serina-Treonina Quinases/genética , Sono/genética , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Obesidade/genética , Obesidade/patologia , Sono/fisiologia
19.
Semin Reprod Med ; 34(4): 215-23, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27513022

RESUMO

In recent years, common genetic variants have been identified by genome-wide association studies (GWASs) that have led to the detection of 44 genetic loci associated with approximately 6% of common variation in age at natural menopause. In the latest GWAS, doubling the sample size to approximately 70,000 women more than doubled the number of signals identified, from 17 to 56. In addition, low-frequency coding variants (< 5% minor allele frequency), with relatively large effect sizes, have been identified in two genes, by analyzing genome-wide exome data. GWAS has been very successful in identifying novel biological pathways involved in reproductive aging. Approximately two-thirds of the loci reported so far include genes involved in DNA damage response (DDR), highlighting the importance of this pathway in determining oocyte reserve. In addition, GWAS demonstrates that the hypothalamic-pituitary axis is involved in menopause timing as well as puberty timing, showing the first genetic link between timing of the start and end of reproductive life. Genetic variants have been used to explore the causal relationships between menopause timing and breast cancer. These studies demonstrate that for a 1 year increase in menopause age, there is a 6% increase in breast cancer risk, a value approximately double the estimate from epidemiological studies. Prolonged exposure to estrogen during reproductive life is the likely mechanism, rather than a direct effect of DDR variants on cancer risk. Further work is needed to determine the mechanism for the effect of each variant identified by GWAS and more variants will undoubtedly be discovered as sample sizes increase, denser single nucleotide polymorphism arrays and reference genomes are used, and populations from diverse ethnic groups are studied.


Assuntos
Estudo de Associação Genômica Ampla , Menopausa/genética , Reprodução/genética , Fatores Etários , Envelhecimento/genética , Neoplasias da Mama/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Feminino , Loci Gênicos , Humanos , Insuficiência Ovariana Primária/genética , Medicina Reprodutiva , Risco
20.
Diabetes ; 65(8): 2448-60, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27207519

RESUMO

Recent genetic studies have identified some alleles that are associated with higher BMI but lower risk of type 2 diabetes, hypertension, and heart disease. These "favorable adiposity" alleles are collectively associated with lower insulin levels and higher subcutaneous-to-visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, to test for interactions between BMI and favorable adiposity genetics, and to test effects separately in men and women. In the UK Biobank, the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 kg/m(2) [95% CI 0.066, 0.174]; P = 1E-5) and higher body fat percentage (0.301% [0.230, 0.372]; P = 1E-16) compared with the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favorable adiposity alleles were at lower risk of type 2 diabetes (odds ratio [OR] 0.837 [0.784, 0.894]; P = 1E-7), hypertension (OR 0.935 [0.911, 0.958]; P = 1E-7), and heart disease (OR 0.921 [0.872, 0.973]; P = 0.003) and had lower blood pressure (systolic -0.859 mmHg [-1.099, -0.618]; P = 3E-12 and diastolic -0.394 mmHg [-0.534, -0.254]; P = 4E-8). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favorable body fat distribution, with a lower waist-to-hip ratio (-0.004 cm [95% CI -0.005, -0.003] 50% vs. 50%; P = 3E-14), but in men, the favorable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267, 0.641] 50% vs. 50%; P = 2E-6) and higher waist-to-hip ratio (0.0013 [0.0003, 0.0024] 50% vs. 50%; P = 0.01). Results were strengthened when a meta-analysis with five additional studies was conducted. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score. In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. Although higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.


Assuntos
Adiposidade/fisiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Cardiopatias/epidemiologia , Hipertensão/epidemiologia , Obesidade/epidemiologia , Adiposidade/genética , Adulto , Idoso , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/etiologia , Feminino , Predisposição Genética para Doença/genética , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Hipertensão/etiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/genética , Razão de Chances , Fatores de Risco , Fatores Sexuais , Circunferência da Cintura , Relação Cintura-Quadril
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