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The Meta-Analysis of Genetic Studies
Published in Christopher H. Schmid, Theo Stijnen, Ian R. White, Handbook of Meta-Analysis, 2020
Cosetta Minelli, John Thompson
While the risk of confounding by population stratification is present in both candidate-gene studies and GWAS, it is only when genome-wide data are available that the problem can be properly investigated and corrected for. In GWAS, the two most widely used approaches to this problem are genomic control and structured association methods. Genomic control (Devlin and Roeder, 1999) is a method for controlling the inflation of test statistics, first developed for binary traits and then generalized for quantitative traits (Bacanu et al., 2002). It uses markers that are not linked with the disease investigated to correct for any exaggeration of statistical significance that is caused by population stratification. Often, QQ-plots are used to illustrate the inflation in the test statistics. We describe these in Section 17.2.5.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The mechanisms by which the CYP2 gene families are transcriptionally activated is unknown. For the CYP2B1 and CYP2B2 (PB-inducible) gene families, it is not clear if a receptor is involved with PB induction since no receptor has been identified, induction requires high doses or exposures, and there are no structural-activity relationships for PB-type induction of P450. Several mechanisms may be involved in the increased transcription of the PB-inducible P450. A hierarchy of cis-acting genomic control elements may influence transcription upon interaction with trans-acting factors, such as PB or other PB-type inducer, heme and/or some other tissue-specific factor. For families CYP3 (steroid or PCN-inducible type) and CYP4 (clofibrate-inducible), similarly to the PB-inducible family, increased gene transcription is believed to be involved in induction (Hardwick et al., 1987). The species-, developmental-, sex-, and tissue-specific expression of P450 activities involve additional regulatory mechanisms. The most likely mechanism(s) for this regulation of P450 activities is transcriptional activation via receptors, trans-and cis-acting genomic control elements, and positive- and negative-acting enhancer elements.
A Retrospective View of the Inherited Errors of the Thyroid System
Published in Geraldo Medeiros-Neto, John Bruton Stanbury, Inherited Disorders of the Thyroid System, 2019
Geraldo Medeiros-Neto, John Bruton Stanbury
An important advance was when, in 1967, Refetoff and his colleagues4 began their studies of members of a family with peripheral resistance to the action of thyroid hormone. In addition to admirable clinical descriptions of the syndrome and its course in this family and a number of others, there have been two thrusts of these investigations. One is the exploitation of the disorder in defining the molecular biology of this abnormality, the analysis of the fine-structure changes in the genes that correspond to the hormone receptors. Perhaps nowhere else in medicine is there so much precise information about the multiple alterations in gene structure and the polymorphism of aberrant molecules involved in phenotypic variation. The other side of this coin is the wealth of information that has flowed from these studies regarding genomic control and the way receptors interact with responsive elements of chromatin.
The transcriptomic revolution and radiation biology
Published in International Journal of Radiation Biology, 2022
The use of different promoters in irradiated cells has also been linked to different translational profiles for those genes (Barak et al. 1994; Rossi et al. 2008). More broadly, a microarray analysis of polysome-bound mRNA found that radiation exposure had a 10-fold greater impact on gene translation than on transcription (Lü et al. 2006). The translational profiles responding to radiation also appear to be tumor type specific, and to differ between tumor and normal cell lines (Kumaraswamy et al. 2008). RNA-Seq analysis of polysome-bound RNA fractions has revealed a 3-fold enhancement of radiation-induced changes in translation of alternative transcripts compared to their transcription, further emphasizing the interconnection between these levels of functional genomic control (Wahba et al. 2018). Translational control and alternative transcription in response to radiation remain understudied areas worthy of more detailed investigation.
Genes involved in glucocorticoid receptor signalling affect susceptibility to mood disorders
Published in The World Journal of Biological Psychiatry, 2021
Dawid Szczepankiewicz, Beata Narożna, Piotr Celichowski, Kosma Sakrajda, Paweł Kołodziejski, Ewa Banach, Przemysław Zakowicz, Ewa Pruszyńska-Oszmałek, Joanna Pawlak, Monika Wiłkość, Monika Dmitrzak-Węglarz, Maria Skibińska, Alicja Bejger, Joanna Twarowska-Hauser, Janusz K. Rybakowski, Leszek Nogowski, Aleksandra Szczepankiewicz
All the assays were validated and predesigned. Reaction components and amplification parameters were based on the manufacturer’s instructions. The amplification for TaqMan SNP genotyping assay plates was done in AbiPrism 7900HT Sequence Detection System. Data acquisition and analysis were performed using the allelic discrimination analysis module in SDS v2.4 software (Applied Biosystems). For each reaction microplate, we included genomic control DNA samples and non-template controls (water). The control of the TaqMan SNP genotyping assay was also performed (15% of randomly chosen samples from both groups) to check for genotyping accuracy and identical genotypes were identified in all repeated samples.
Circulating levels of the anti-oxidant indoleproprionic acid are associated with higher gut microbiome diversity
Published in Gut Microbes, 2019
Cristina Menni, Marisa Matey Hernandez, Marius Vital, Robert P. Mohney, Tim D. Spector, Ana M. Valdes
Genetic variation: Here we dissected the IPA genome-wide association scan (GWAS) data that was previously generated and published as part of our GWAS–metabolomics study.8 GWAS (in the HapMap 2–based imputed genotype data set) was conducted on 6056 individuals from TwinsUK and 1768 from KORA as previously described.8 Association results were combined in Metal18 using inverse variance meta-analysis based on effect size estimates and standard errors, adjusting for genomic control.