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1.
Diabetes ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506345

RESUMO

Extreme obesity (EO, BMI>50) 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 (PTV) and copy number variants (CNV) 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, n=374) and a Swedish cohort of participants from the community with predominantly O (n=161). The prevalence of variants was compared to controls in ExAC/gnomAd database.In the discovery cohort (high NPD prevalence: 77%), the cumulative PTV/CNV allele frequency (AF) was 7.7 % vs 2.6% in controls (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 controls, 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 PTV/CNVs, in genes/regions previously associated with NPD, may contribute to NPD in patients with EO.

2.
Genet Epidemiol ; 43(7): 815-830, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31332826

RESUMO

Genotype-stratified variance of a quantitative trait could differ in the presence of gene-gene or gene-environment interactions. Genetic markers associated with phenotypic variance are thus considered promising candidates for follow-up interaction or joint location-scale analyses. However, as in studies of main effects, the X-chromosome is routinely excluded from "whole-genome" scans due to analytical challenges. Specifically, as males carry only one copy of the X-chromosome, the inherent sex-genotype dependency could bias the trait-genotype association, through sexual dimorphism in quantitative traits with sex-specific means or variances. Here we investigate phenotypic variance heterogeneity associated with X-chromosome single nucleotide polymorphisms (SNPs) and propose valid and powerful strategies. Among those, a generalized Levene's test has adequate power and remains robust to sexual dimorphism. An alternative approach is a sex-stratified analysis but at the cost of slightly reduced power and modeling flexibility. We applied both methods to an Estonian study of gene expression quantitative trait loci (eQTL; n = 841), and two complex trait studies of height, hip, and waist circumferences, and body mass index from Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,073) and UK Biobank (UKB; n = 327,393). Consistent with previous eQTL findings on mean, we found some but no conclusive evidence for cis regulators being enriched for variance association. SNP rs2681646 is associated with variance of waist circumference (p = 9.5E-07) at X-chromosome-wide significance in UKB, with a suggestive female-specific effect in MESA (p = 0.048). Collectively, an enrichment analysis using permutated UKB (p < 0.1) and MESA (p < 0.01) datasets, suggests a possible polygenic structure for the variance of human height.

3.
BMC Cancer ; 19(1): 557, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182048

RESUMO

BACKGROUND: Published genetic risk scores for breast cancer (BC) so far have been based on a relatively small number of markers and are not necessarily using the full potential of large-scale Genome-Wide Association Studies. This study aimed to identify an efficient polygenic predictor for BC based on best available evidence and to assess its potential for personalized risk prediction and screening strategies. METHODS: Four different genetic risk scores (two already published and two newly developed) and their combinations (metaGRS) were compared in the subsets of two population-based biobank cohorts: the UK Biobank (UKBB, 3157 BC cases, 43,827 controls) and Estonian Biobank (EstBB, 317 prevalent and 308 incident BC cases in 32,557 women). In addition, correlations between different genetic risk scores and their associations with BC risk factors were studied in both cohorts. RESULTS: The metaGRS that combines two genetic risk scores (metaGRS2 - based on 75 and 898 Single Nucleotide Polymorphisms, respectively) had the strongest association with prevalent BC status in both cohorts. One standard deviation difference in the metaGRS2 corresponded to an Odds Ratio = 1.6 (95% CI 1.54 to 1.66, p = 9.7*10- 135) in the UK Biobank and accounting for family history marginally attenuated the effect (Odds Ratio = 1.58, 95% CI 1.53 to 1.64, p = 7.8*10- 129). In the EstBB cohort, the hazard ratio of incident BC for the women in the top 5% of the metaGRS2 compared to women in the lowest 50% was 4.2 (95% CI 2.8 to 6.2, p = 8.1*10- 13). The different GRSs were only moderately correlated with each other and were associated with different known predictors of BC. The classification of genetic risk for the same individual varied considerably depending on the chosen GRS. CONCLUSIONS: We have shown that metaGRS2, that combined on the effects of more than 900 SNPs, provided best predictive ability for breast cancer in two different population-based cohorts. The strength of the effect of metaGRS2 indicates that the GRS could potentially be used to develop more efficient strategies for breast cancer screening for genotyped women.

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

RESUMO

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

5.
Curr Biol ; 29(10): 1701-1711.e16, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31080083

RESUMO

In this study, we compare the genetic ancestry of individuals from two as yet genetically unstudied cultural traditions in Estonia in the context of available modern and ancient datasets: 15 from the Late Bronze Age stone-cist graves (1200-400 BC) (EstBA) and 6 from the Pre-Roman Iron Age tarand cemeteries (800/500 BC-50 AD) (EstIA). We also included 5 Pre-Roman to Roman Iron Age Ingrian (500 BC-450 AD) (IngIA) and 7 Middle Age Estonian (1200-1600 AD) (EstMA) individuals to build a dataset for studying the demographic history of the northern parts of the Eastern Baltic from the earliest layer of Mesolithic to modern times. Our findings are consistent with EstBA receiving gene flow from regions with strong Western hunter-gatherer (WHG) affinities and EstIA from populations related to modern Siberians. The latter inference is in accordance with Y chromosome (chrY) distributions in present day populations of the Eastern Baltic, as well as patterns of autosomal variation in the majority of the westernmost Uralic speakers [1-5]. This ancestry reached the coasts of the Baltic Sea no later than the mid-first millennium BC; i.e., in the same time window as the diversification of west Uralic (Finnic) languages [6]. Furthermore, phenotypic traits often associated with modern Northern Europeans, like light eyes, hair, and skin, as well as lactose tolerance, can be traced back to the Bronze Age in the Eastern Baltic. VIDEO ABSTRACT.

6.
PLoS One ; 14(4): e0215026, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30978214

RESUMO

The Estonian Biobank, governed by the Institute of Genomics at the University of Tartu (Biobank), has stored genetic material/DNA and continuously collected data since 2002 on a total of 52,274 individuals representing ~5% of the Estonian adult population and is increasing. To explore the utility of data available in the Biobank, we conducted a phenome-wide association study (PheWAS) in two areas of interest to healthcare researchers; asthma and liver disease. We used 11 asthma and 13 liver disease-associated single nucleotide polymorphisms (SNPs), identified from published genome-wide association studies, to test our ability to detect established associations. We confirmed 2 asthma and 5 liver disease associated variants at nominal significance and directionally consistent with published results. We found 2 associations that were opposite to what was published before (rs4374383:AA increases risk of NASH/NAFLD, rs11597086 increases ALT level). Three SNP-diagnosis pairs passed the phenome-wide significance threshold: rs9273349 and E06 (thyroiditis, p = 5.50x10-8); rs9273349 and E10 (type-1 diabetes, p = 2.60x10-7); and rs2281135 and K76 (non-alcoholic liver diseases, including NAFLD, p = 4.10x10-7). We have validated our approach and confirmed the quality of the data for these conditions. Importantly, we demonstrate that the extensive amount of genetic and medical information from the Estonian Biobank can be successfully utilized for scientific research.

7.
Sci Rep ; 9(1): 5849, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971755

RESUMO

Haplotype-based methods are a cost-effective alternative to characterize unobserved rare variants and map disease-associated alleles. Moreover, they can be used to reconstruct recent population history, which shaped distribution of rare variants and thus can be used to guide gene mapping studies. In this study, we analysed Illumina 650 k genotyped dataset on three underrepresented populations from Eastern Europe, where ancestors of Russians came into contact with two indigenous ethnic groups, Bashkirs and Tatars. Using the IBD mapping approach, we identified two rare IBD haplotypes strongly enriched in asthma patients of distinct ethnic background. We reconstructed recent population history using haplotype-based methods to reconcile this contradictory finding. Our ChromoPainter analysis showed that these haplotypes each descend from a single ancestor coming from one of the ethnic groups studied. Next, we used DoRIS approach and showed that source populations for patients exchanged recent (<60 generations) asymmetric gene flow, which supported the ChromoPainter-based scenario that patients share haplotypes through inter-ethnic admixture. Finally, we show that these IBD haplotypes overlap with asthma-associated genomic regions ascertained in European population. This finding is consistent with the fact that the two donor populations for the rare IBD haplotypes: Russians and Tatars have European ancestry.

8.
Int J Immunogenet ; 46(2): 49-58, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659741

RESUMO

Allele-specific analyses to understand frequency differences across populations, particularly populations not well studied, are important to help identify variants that may have a functional effect on disease mechanisms and phenotypic predisposition, facilitating new Genome-Wide Association Studies (GWAS). We aimed to compare the allele frequency of 11 asthma-associated and 16 liver disease-associated single nucleotide polymorphisms (SNPs) between the Estonian, HapMap and 1000 genome project populations. When comparing EGCUT with HapMap populations, the largest difference in allele frequencies was observed with the Maasai population in Kinyawa, Kenya, with 12 SNP variants reporting statistical significance. Similarly, when comparing EGCUT with 1000 genomes project populations, the largest difference in allele frequencies was observed with pooled African populations with 22 SNP variants reporting statistical significance. For 11 asthma-associated and 16 liver disease-associated SNPs, Estonians are genetically similar to other European populations but significantly different from African populations. Understanding differences in genetic architecture between ethnic populations is important to facilitate new GWAS targeted at underserved ethnic groups to enable novel genetic findings to aid the development of new therapies to reduce morbidity and mortality.


Assuntos
Asma/genética , Frequência do Gene/genética , Genética Populacional , Genoma Humano , Projeto HapMap , Hepatopatias/genética , Polimorfismo de Nucleotídeo Único/genética , Estônia , Humanos
9.
Nat Genet ; 51(2): 237-244, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643251

RESUMO

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Fumar/genética , Tabagismo/genética , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Risco , Tabaco/efeitos adversos
10.
Am J Hum Genet ; 104(1): 157-163, 2019 Jan 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.

11.
PLoS Genet ; 14(12): e1007813, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566500

RESUMO

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.


Assuntos
Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
13.
Eur J Hum Genet ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420678

RESUMO

Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel loss-of-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery.

14.
Genet Med ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30270359

RESUMO

PURPOSE: Large-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy. METHODS: The Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants. RESULTS: Via genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations. CONCLUSION: Genotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.

15.
Hum Reprod ; 33(11): 2074-2086, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295736

RESUMO

STUDY QUESTION: Does cellular composition of the endometrial biopsy affect the gene expression profile of endometrial whole-tissue samples? SUMMARY ANSWER: The differences in epithelial and stromal cell proportions in endometrial biopsies modify the whole-tissue gene expression profiles and affect the results of differential expression analyses. WHAT IS ALREADY KNOWN: Each cell type has its unique gene expression profile. The proportions of epithelial and stromal cells vary in endometrial tissue during the menstrual cycle, along with individual and technical variation due to the method and tools used to obtain the tissue biopsy. STUDY DESIGN, SIZE, DURATION: Using cell-population specific transcriptome data and computational deconvolution approach, we estimated the epithelial and stromal cell proportions in whole-tissue biopsies taken during early secretory and mid-secretory phases. The estimated cellular proportions were used as covariates in whole-tissue differential gene expression analysis. Endometrial transcriptomes before and after deconvolution were compared and analysed in biological context. PARTICIPANTS/MATERIAL, SETTING, METHODS: Paired early- and mid-secretory endometrial biopsies were obtained from 35 healthy, regularly cycling, fertile volunteers, aged 23-36 years, and analysed by RNA sequencing. Differential gene expression analysis was performed using two approaches. In one of them, computational deconvolution was applied as an intermediate step to adjust for the proportions of epithelial and stromal cells in the endometrial biopsy. The results were then compared to conventional differential expression analysis. Ten paired endometrial samples were analysed with qPCR to validate the results. MAIN RESULTS AND THE ROLE OF CHANCE: The estimated average proportions of stromal and epithelial cells in early secretory phase were 65% and 35%, and during mid-secretory phase, 46% and 54%, respectively, correlating well with the results of histological evaluation (r = 0.88, P = 1.1 × 10-6). Endometrial tissue transcriptomic analysis showed that approximately 26% of transcripts (n = 946) differentially expressed in receptive endometrium in cell-type unadjusted analysis also remain differentially expressed after adjustment for biopsy cellular composition. However, the other 74% (n = 2645) become statistically non-significant after adjustment for biopsy cellular composition, underlining the impact of tissue heterogeneity on differential expression analysis. The results suggest new mechanisms involved in endometrial maturation, involving genes like LINC01320, SLC8A1 and GGTA1P, described for the first time in context of endometrial receptivity. LARGE-SCALE DATA: The RNA-seq data presented in this study is deposited in the Gene Expression Omnibus database with accession number GSE98386. LIMITATIONS REASONS FOR CAUTION: Only dominant endometrial cell types were considered in gene expression profile deconvolution; however, other less frequent endometrial cell types also contribute to the whole-tissue gene expression profile. WIDER IMPLICATIONS OF THE FINDINGS: The better understanding of molecular processes during transition from pre-receptive to receptive endometrium serves to improve the effectiveness and personalization of assisted reproduction protocols. Biopsy cellular composition should be taken into account in future endometrial 'omics' studies, where tissue heterogeneity could potentially influence the results. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by: Estonian Ministry of Education and Research (grant IUT34-16); Enterprise Estonia (EU48695); the EU-FP7 Eurostars program (NOTED, EU41564); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (SARM, EU324509); Horizon 2020 innovation program (WIDENLIFE, EU692065); MSCA-RISE-2015 project MOMENDO (No 691058) and the Miguel Servet Program Type I of Instituto de Salud Carlos III (CP13/00038); Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526. Authors confirm no competing interests.

16.
Nat Genet ; 50(11): 1505-1513, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30297969

RESUMO

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

17.
Genet Med ; 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30327539

RESUMO

PURPOSE: Biomedical databases combining electronic medical records and phenotypic and genomic data constitute a powerful resource for the personalization of treatment. To leverage the wealth of information provided, algorithms are required that systematically translate the contained information into treatment recommendations based on existing genotype-phenotype associations. METHODS: We developed and tested algorithms for translation of preexisting genotype data of over 44,000 participants of the Estonian biobank into pharmacogenetic recommendations. We compared the results obtained by genome sequencing, exome sequencing, and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia. RESULTS: Our most striking result was that the performance of genotyping arrays is similar to that of genome sequencing, whereas exome sequencing is not suitable for pharmacogenetic predictions. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants. CONCLUSION: We find that microarrays are a cost-effective solution for creating preemptive pharmacogenetic reports, and with slight modifications, existing databases can be applied for automated pharmacogenetic decision support for clinicians.

18.
Hum Mol Genet ; 27(24): 4323-4332, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30202859

RESUMO

The normal menstrual cycle requires a delicate interplay between the hypothalamus, pituitary and ovary. Therefore, its length is an important indicator of female reproductive health. Menstrual cycle length has been shown to be partially controlled by genetic factors, especially in the follicle-stimulating hormone beta-subunit (FSHB) locus. A genome-wide association study meta-analysis of menstrual cycle length in 44 871 women of European ancestry confirmed the previously observed association with the FSHB locus and identified four additional novel signals in, or near, the GNRH1, PGR, NR5A2 and INS-IGF2 genes. These findings not only confirm the role of the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length but also highlight potential novel local regulatory mechanisms, such as those mediated by IGF2.

19.
Biomark Med ; 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30191727

RESUMO

AIM: The aim of the study was to explore the effects of variants at 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and kinesin family member 6 (KIF6) loci on a range of cardio-metabolic phenotypes. METHODS: We analyzed the range of variants within Genetics in Brisighella Health Study and KIF6 genes using an additive genetic model on 18 cardiometabolic phenotypes in a sample of 1645 individuals from the Genetics in Brisighella Health Study and replicated in 10,662 individuals from the Estonian Genome Center University of Tartu. RESULTS: We defined directly the effects of rs3846662:C>A at HMGCR on apoB levels. The analysis also confirmed effects of on low-density lipoprotein-cholesterol and total cholesterol levels. Variants in KIF6 gene did not reveal any associations with cardiometabolic phenotypes. CONCLUSION: This study highlights effect of HMGCR locus on assay-determined apoB levels, an infrequent measure of blood lipids in large studies.

20.
Nat Genet ; 50(10): 1412-1425, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

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