913 research outputs found
Modulation of genetic associations with serum urate levels by body-mass-index in humans
No full textWe tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.</p
Negative effect of vitamin D on kidney function: a Mendelian randomization study
No full textBACKGROUND:
The kidney plays a central role in the regulation of vitamin D metabolism. It is not clear, however, whether vitamin D influences kidney function. Previous studies have reported conflicting results, which may have been influenced by reverse causation and residual confounding. We conducted a Mendelian randomization (MR) study to obtain unconfounded estimates of the association between genetically instrumented vitamin D metabolites and estimated glomerular filtration rate (eGFR) as well as the urinary albumin:creatinine ratio (UACR).
METHODS:
We performed a two-sample MR study based on three single nucleotide variants associated with 25(OH)D levels: rs2282679, rs10741657 and rs12785878, related to the genes GC, CYP2R1 and DHCR7, respectively. Estimates of the allele-dependent effects on serum 25(OH)D and eGFR/UACR were obtained from summary statistics of published genome-wide association meta-analyses. Additionally, we performed a one-sample MR analysis for both 25(OH)D and 1,25(OH)2 D using individual-level data from six cohorts.
RESULTS:
The combined MR estimate supported a negative causal effect of log transformed 25(OH)D on log transformed eGFR (β = -0.013, P = 0.003). The analysis of individual-level data confirmed the main findings and also revealed a significant association of 1,25(OH)2 D on eGFR (β = -0.094, P = 0.008). These results show that a 10% increase in serum 25(OH)D levels causes a 0.3% decrease in eGFR. There was no effect of 25(OH)D on UACR (β = 0.032, P = 0.265).
CONCLUSION:
Our study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR. Further studies are needed to elucidate the underlying mechanisms
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
No full textApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups
Copy number variations and cognitive phenotypes in unselected populations
No full textIMPORTANCE The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency≤0.05%; size≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS The population biobank of Estonia contains 52 000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health-and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES Phenotypes of genomic disorders in the general population, prevalence of autosomalCNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%;≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95%CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1Mb (OR, 3.67; 95%CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainmentwas 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5%did not graduate from high school (OR, 1.48; 95%CI, 1.12-1.95; P = .005) and 39.1%of duplication carriers did not graduate high school (OR, 1.89; 95%CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainmentwas supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVsmay be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health
Analyzing illumina gene expression microarray data obtained from human whole blood cell and blood monocyte samples.
No full textMicroarray profiling of gene expression is widely applied to studies in molecular biology and functional genomics. Experimental and technical variations make not only the statistical analysis of single studies but also meta-analyses of different studies very challenging. Here, we describe the analytical steps required to substantially reduce the variations of gene expression data without affecting true effect sizes. A software pipeline has been established using gene expression data from a total of 3358 whole blood cell and blood monocyte samples, all from three German population-based cohorts, measured on the Illumina HumanHT-12 v3 BeadChip array. In summary, adjustment for a few selected technical factors greatly improved reliability of gene expression analyses. Such adjustments are particularly required for meta-analyses of different studies
Interactions Between Genetic Variants in Glucose Transporter Type 9 (SLC2A9) and Dietary Habits in Serum Uric Acid Regulation
No full textAim To investigate possible interactions between genetic
variants in glucose transporter type 9 (SLC2A9) gene and
dietary habits in serum uric acid regulation.
Methods Participants for this study were recruited from
two isolated Croatian island communities of Vis (n = 918)
and Korčula (n = 898). Three single nucleotide polymorphisms
(SNP) from the SLC2A9 gene (rs1014290, rs6449213,
rs737267) were correlated with dietary habits and uric
acid.
Results A significant decrease in uric acid levels was recorded
with increasing consumption of milk, sour cream,
duck and turkey, and eggs. The only significant interaction
was found between potato consumption and rs737267
and a near-significant interaction was found between soft
drinks and rs1014290 (interaction P = 0.068). Increased
consumption of soft drinks interacting with the TT genotype
at rs1014290 increased serum uric acid. No significant
interactions were observed between food products consumption
and rs6449213.
Conclusion There is a certain extent of interaction between
SLC2A9 and dietary patterns in serum uric acid determination.
The metabolic effect of soft drinks seems to
be determined by the underlying genotype of rs1014290
Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index
No full textThe phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ~4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity. © 2014 Hoggart et al
Microarray-based Genome-Wide Association Studies (GWAS) using data generated by Allelotyping and by individual Genotyping
No full textGenome-wide association studies (GWAS) are used to identify genetic markers linked with at least partially heritable diseases or phenotypes without prior knowledge of any disease-associated genetic loci. In summer 2008, all individuals of the population based cohort Study of Health in Pomerania (SHIP) were individually genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0 microarray. The aim of this work was to establish an efficient workflow for GWAS using the more than 4000 individually genotyped samples of the SHIP cohort as well as pooled samples, focusing exclusively on analyzing genetic variations based on single nucleotide polymorphisms (SNPs). Firstly, an optimal array platform for the genotyping analysis had to be chosen that detected most of the available genetic variants at a high level of accuracy. Secondly, extensive quality controls had to be performed starting from DNA extraction and including tests of the generated array data by the analysis software to obtain the most reliable data for the subsequent association studies. For the identification of loci with smaller genetic influences, individual cohorts were meta-analyzed in large nationally and internationally organized consortia (e.g. CHARGE, BPGen, HaemGen, GIANT, CKD Gen). To participate in those meta-analyses, a comparable common set of genetic data had to be generated. This was done by imputation of the data generated by individual array-based genotyping on the basis of a reference panel using chromosomal linkage information. Due to the extensive phenotype information in the SHIP study, it was possible to perform many genome-wide discovery analyses and replication studies of possible susceptibility loci in a short time once the genetic data was available and processed. This resulted in the necessity to set up an efficient workflow for storing the huge amount of genetic data, converting it into different formats readable for specific analysis software, performing the association analyses and processing the results into a human-readable and clear format. This included replications, GWAS and meta-analyses of several cohorts. Many susceptibility loci were newly identified in different association studies with the SHIP data included and were subsequently published. In this work, genetic association studies with the SHIP data included were performed and published on blood pressure, uric acid concentrations, cardiac structure and function, lipid metabolism, hematological parameters, kidney functions, smoking quantity, circulating IGF-I and IGFBP-3 concentrations and thyroid volume including the risk of goiter development. Besides the SHIP cohort, there was a need to use other, especially patient cohorts for GWAS. Since no genotype information from these patient cohorts was available and the individual genotyping of many probands is still expensive and therefore often not affordable, we established the cost-effective allelotyping method that relied on pooling of DNA samples prior to the hybridization with microarrays. After estimating the pooling-specific error of a case-control allelotyping study, the allelotyping approach was used for identifying genetic susceptibility loci associated with aggressive periodontitis. If not referring to work of collaborators, all statistical analyses, data handling and in silico work concerning the SHIP data described in this context was performed by the author of this dissertation.Genomweite Assoziationsstudien (GWAS) werden verwendet, um genetische Marker zu identifizieren, die mit zumindest teilweise vererbbaren Krankheiten oder Phänotypen assoziiert sind, ohne dabei vorab Informationen von bekannten krankheits-assoziierten genetischen Loci zu berücksichtigen. Im Sommer 2008 wurden alle Personen der bevölkerungsbasierten Kohorte Study of Health in Pomerania (SHIP) individuell mit Hilfe des Affymetrix Genome-Wide Human SNP Array 6.0 genotypisiert. Das Ziel dieser Arbeit war es, einen effizienten Workflow für GWAS basierend auf den mehr als 4000 einzeln genotypisierten Probanden der SHIP Kohorte sowie gepoolten DNA-Proben zu schaffen, wobei sich ausschließlich auf die Analyse genetischer Variationen von Einzelbasen-Polymorphismen (SNPs) beschränkt wurde. Zuerst mußte eine optimale Array-Plattform für die Genotypisierung ausgewählt werden, die die meisten bekannten genetischen Varianten mit hoher Genauigkeit detektieren kann. Zweitens mußten umfangreiche Qualitätskontrollen durchgeführt werden, beginnend bei der DNA-Extraktion bis hin zu Tests der durch die Analyse-Software erzeugten Array-Daten, um verlässliche Daten für die nachfolgenden Assoziationsstudien zu erhalten. Für die Identifizierung von Loci mit kleineren genetischen Einflüssen wurden Ergebnisse einzelner Kohorten in großen national und international organisierten Konsortien meta-analysiert (z.B. CHARGE, BPGen, HaemGen, GIANT, CKD Gen). Zur Teilnahme an diesen Meta-Analysen, mußte eine gemeinsame Basis genetischer Daten erzeugt werden. Dieses wurde durch sogenannte Imputation der Daten der einzelnen Array-basierten Genotypisierungen auf der Grundlage eines Referenz-Panels unter Berücksichtigung chromosomaler Kopplungsinformationen durchgeführt. Aufgrund der umfangreichen Phänotypinformationen der SHIP-Studie war es möglich, viele genomweite Analysen und Replikationsstudien zur Endeckung genetischer Anfälligkeits-Loci in kurzer Zeit durchzuführen, sobald die genetischen Daten zur Verfügung standen. Dafür war es notwendig, einen effizienten Workflow zur Speicherung der enormen Menge genetischer Informationen, deren Konvertierung in andere Formate welche lesbar für die spezielle Analyse-Software sind, die Durchführung der Assoziationsstudien und die Aufarbeitung der Ergebnisse in ein lesbares und übersichtliches Format zu erstellen. Dazu gehörten Replikationen, GWAS und Meta-Analysen von mehreren Kohorten. Viele neue Anfälligkeits-Loci konnten dabei in verschiedenen Assoziationsstudien unter Einbeziehung der SHIP-Daten identifiziert und anschließend veröffentlicht werden. In dieser Arbeit sind genetische Assoziationsstudien aufgeführt, die basieren auf Blutdruckdaten, Harnsäure-Konzentration, Herz-Struktur und -funktion, Fettstoffwechsel, hämatologischen Parametern, Nierenfunktion, Rauchen, IGF-I und IGFBP-3-Konzentrationen und Schilddrüsen-Volumen einschließlich des Risikos der Kropfbildung unter Einbeziehung der SHIP-Daten durchgeführt und veröffentlicht wurden. Neben der SHIP Kohorte gab es die Notwendigkeit GWAS in anderen Gruppen, besonders in Patientengruppen durchzuführen. Da keine Genotypinformationen aus diesen Patientengruppen zur Verfügung standen und die individuelle Genotypisierung von vielen Probanden noch teuer und daher oft nicht erschwinglich war, haben wir die kostengünstige Allelotypisierungs-Methode, die auf dem Poolen von DNA-Proben vor der Hybridisierung mit Microarrays basiert, umgesetzt. Nach Schätzung des pooling-spezifischen Fehlers anhand einer Fall-Kontroll-Allelotypisierungsstudie, wurde der Allelotypisierungsansatz zur Ermittlung genetischer Anfälligkeits-Loci, welche mit aggressiver Parodontitis assoziiert sind, angewendet. Falls nicht auf die Arbeit von Kooperatoren referenziert wurde, sind alle hier beschriebenen statistischen Analysen, die Datenverarbeitung und die in silico Arbeit basierend auf den SHIP-Daten vom Autor dieser Dissertation durchgeführt worden
Common variants in mendelian kidney disease genes and their association with renal function
No full textMany common genetic variants identified by genome-wide association studies for complex traitsmap to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.open
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