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1.  Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas 
Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC).
We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model‐based and model‐free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model‐based linkage analysis. Model‐based and model‐free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome‐wide associations were also tested in these families.
Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female‐affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported.
Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.
PMCID: PMC4947860  PMID: 27468417
Barrett's esophagus; esophageal adenocarcinoma; familial; genetics; linkage
2.  A Segregation Analysis of Barrett’s Esophagus and Associated Adenocarcinomas 
Familial aggregation of esophageal adenocarcinomas, esophagogastric junction adenocarcinomas, and their precursor Barrett’s esophagus has been termed Familial Barrett’s Esophagus (FBE). Numerous studies documenting increased familial risk for these diseases raise the hypothesis that there may be an inherited susceptibility to the development of BE and its associated cancers. In this study, using segregation analysis for a binary trait as implemented in S.A.G.E. 6.0.1, we analyzed data on 881singly ascertained pedigrees in order to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE. The inheritance models were compared by likelihood ratio tests and Akaike’s A Information Criterion. Results indicated that random environmental and/or multifactorial components were insufficient to fully explain the familial nature of FBE, but rather there is segregation of a major type transmitted from one generation to the next (p-value < 10−10). An incompletely dominant inheritance model together with a polygenic component fits the data best. For this dominant model, the estimated penetrance of the dominant allele is 0.1005 (95% confidence interval, CI: 0.0587 to 0.1667) and the sporadic rate is 0.0012 (95% CI: 0.0004 to 0.0042), corresponding to a relative risk of 82.53 (95% CI: 28.70 to 237.35), or odds ratio of 91.63 (95% CI: 32.01 to 262.29). This segregation analysis provides epidemiological evidence in support of one or more rare autosomally inherited dominant susceptibility allele(s) in FBE families, and hence motivates linkage analyses.
PMCID: PMC2838211  PMID: 20200424
familial esophageal adenocarcinomas; complex segregation analysis; dominant major gene inheritance; polygenic component; likelihood; AIC; unified model

Results 1-2 (2)