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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 these methods only allow hypothesis testing, Gu et al. first proposed a method that provides a pooled estimate of the genetic effect based on the proportion of alleles shared identical-by-descent (IBD) (Gu et al., 1998), although the requirements of similarity in markers genotyped and availability of IBD sharing statistics from the published genome scans may limit its applicability in practice. Other approaches have been subsequently proposed to combine effect estimates from published genome scans (Kippola and Santorico, 2010). It is important to note that even the meta-analysis of genome scans using raw data, often considered as the gold standard, is problematic when different marker panels are used, since this introduces a systematic difference in IBD estimates between studies (Dempfle and Loesgen, 2004).
Molecular Genetic Approaches to Obesity
Published in Claude Bouchard, The Genetics of Obesity, 2020
Streamson C. Chua, Rudolph L. Leibel
Since it is likely that obesity is polygenic in man — or at least that different genes are responsible in different families — segregation analysis of families from diverse genetic backgrounds is unlikely to be fruitful. The ultimate goal of such analyses is to indicate the likely mode of inheritance of those genes with major influence on the risk of development of obesity. Such information may be used, in turn, to direct linkage analyses designed to identify specific genes or regions of the genome which confer such risk. The high likelihood of genetic heterogeneity, and of epistatic interaction of relevant genes, favors the initial use of linkage methods which are not dependent on prior knowledge of the mode(s) of inheritance. Affected sib pair analysis — in which affected siblings are examined for the inheritance of alleles linked to the phenotype of interest — is an example of such a model-free method.5 A fully informative locus unlinked to the disease should be coinherited in Mendelian ratios of 1:2:1 for two, one, or zero alleles, respectively. If the marker allele is linked to the gene responsible for the phenotype, the likelihood of sib pair identity by descent (IBD) for two alleles is increased while the likelihood of IBD for zero alleles is reduced. IBD for a locus refers to the inheritance by sibs of identical alleles from a common ancestor.
Assigning the LR
Published in Jo-Anne Bright, Michael D. Coble, Forensic DNA Profiling, 2019
Jo-Anne Bright, Michael D. Coble
Of interest in a forensic DNA context is inbreeding. Inbreeding is when individuals mate who are more closely related than if they had been chosen at random from a population. Related individuals have ancestors in common (coancestry), and their offspring are more likely to inherit the same copy of an ancestral allele from each parent (these alleles are described as being identical by descent [IBD]). Inbreeding may be due to religious or language reasons and rates increase in smaller populations. Inbreeding leads to an increased number of homozygotes within the population compared with expectation.
Personalizing therapy selection in inflammatory bowel disease
Published in Expert Review of Clinical Immunology, 2023
Many lessons have been learned from the use of mAbs over the last 20 years. In the clinical trial setting, with rigorous end-points, remission rates from targeting TNF, IL-23, or lymphocyte trafficking have failed to exceed ~30% during the induction phase [3]. This suggests that a mono-pathway treatment approach to these complex conditions serves a limited set of patients. It also informs the need for drug selection based on more than just the presence of a diagnosis of IBD. Secondly, maintenance of remission using mAbs has suffered from a decline in sustainability over time, either due to immunogenicity, or a shift in dominant inflammatory pathways. Anti-drug antibody (ADA) prevalence as high as 60% was seen with initial use of infliximab, although newer mAbs are associated with ADA rates less than 10% during the maintenance phase [25,26]. The shift in inflammatory pathways has been more complicated to delineate in vivo. As an example, patients exposed to anti-TNFs exhibit significant upregulation of pro-inflammatory genes such as CXCR2, CXCL5, S100A8/9 (fecal calprotectin), OSM, and IL22RA1 in colonic biopsies. [27,28] Thankfully, agents that target JAK1 (tofacitinib, upadacitinib) can still inhibit cytokine production in phagocytes isolated from biopsy specimens of patients with IBD who have lost response to anti-TNF mAbs [28,29]. These lessons, from mAbs and patient samples, have spurred an interest in identifying patient and treatment-related factors that could be harnessed to personalize treatment decisions in IBD.
The oft-overlooked cardiovascular complications of inflammatory bowel disease
Published in Expert Review of Clinical Immunology, 2023
Sara Massironi, Giacomo Mulinacci, Camilla Gallo, Chiara Viganò, Maria Fichera, Andrea Villatore, Giovanni Peretto, Silvio Danese
Furthermore, the rapid increase in production of genetic data from new sequencing technologies aided the recognition of myriad of genetic variations, most commonly single nucleotide polymorphisms (SNPs) in candidate genes. A number of SNPs proved to be associated to IBD, being either predisposing or protecting factors from disease onset [29]. Similarly, several genetic risk factors predispose to CVD [30]. Naito et al. recently combined whole exome sequencing and whole-genome genotyping, and recognized specific genetic traits able to identify a subset of IBD patients at higher risk for VTE [31]. Polymorphisms in Factor V Leiden, G20210A and plasminogen activator inhibitor 1 (PAI 1) increase the risk of VTE among IBD patients, even if mutation frequency in IBD patients was not higher than controls [31,32].
Linkage analysis identifies novel genetic modifiers of microbiome traits in families with inflammatory bowel disease
Published in Gut Microbes, 2022
Arunabh Sharma, Silke Szymczak, Malte Rühlemann, Sandra Freitag-Wolf, Carolin Knecht, Janna Enderle, Stefan Schreiber, Andre Franke, Wolfgang Lieb, Michael Krawczak, Astrid Dempfle
Reported family relationships were evaluated for consistency based upon the available SNP genotypes, using different strategies. First, possible relatedness between families was assessed considering the most likely level of identity-by descent (ibd) between pairs of presumably unrelated individuals from different families, estimated with PLINK from 50k SNPs with MAF >0.05 and pairwise linkage disequilibrium (LD) <0.1. Second, relationships within pedigrees were assessed for correctness with a maximized log-likelihood ratio (MLLR) test as implemented in PREST (v3_02),43 using 5k SNPs with MAF >0.1 and pairwise LD <0.1. Third, potentially false relationships were checked further with ALTERTEST (v3_02),43 using 2k SNPs with MAF >0.1 and pairwise LD <0.1 where the reduction in marker number became necessary due to the computational complexity and demand of the analysis. As a result, one pair of presumably unrelated individuals was removed because they could have been first cousins or at least distantly related, according to ALTERTEST. In addition, the genotypes of two samples involved in a potential sample swap were set to missing.