PMCC PMCC

Conseils de recherche
Les critères de recherche

Avancée
Résultats 1-5 (5)
 

Notices sélectionnées (0)
Aucune

Sélectionner un filtre

Revues
Année de publication
Type de document
author:("Sun, xiangdong")
1.  A variable age of onset segregation model for linkage analysis, with correction for ascertainment, applied to glioma 
Background
We propose a two-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma.
Methods
First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N=281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N=74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are re-estimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis.
Results
Using the best fitting segregation models in model-based multipoint linkage analysis, we identified two separate peaks on chromosome 17; the first agreed with a region identified by Shete et al. who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD).
Conclusions/Impact
Our approach has the advantage of not requiring markers to be in linkage equilibrium unless the minor allele frequency is small (markers which tend to be uninformative for linkage), and of using more of the available information for LOD-based linkage analysis.
doi:10.1158/1055-9965.EPI-12-0703
PMCID: PMC3518573  PMID: 22962404
Glioma; model-based linkage; segregation; age of onset; prevalence constraint
2.  Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia 
Human genetics  2011;130(5):635-643.
Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDβH. Prior studies have suggested that variation in pDβH, or genetic variants at DβH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDβH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDβH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pDβH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDβH, and suggest that a locus near 20p12 also influences pDβH.
doi:10.1007/s00439-011-0989-6
PMCID: PMC3193571  PMID: 21509519
3.  Capability of common SNPs to tag rare variants 
BMC Proceedings  2011;5(Suppl 9):S88.
Genome-wide association studies are based on the linkage disequilibrium pattern between common tagging single-nucleotide polymorphisms (SNPs) (i.e., SNPs having only common alleles) and true causal variants, and association studies with rare SNP alleles aim to detect rare causal variants. To better understand and explain the findings from both types of studies and to provide clues to improve the power of an association study with only common SNPs genotyped, we study the correlation between common SNPs and the presence of rare alleles within a region in the genome and look at the capability of common SNPs in strong linkage disequilibrium with each other to capture single rare alleles. Our results indicate that common SNPs can, to some extent, tag the presence of rare alleles and that including SNPs in strong linkage disequilibrium with each other among the tagging SNPs helps to detect rare alleles.
doi:10.1186/1753-6561-5-S9-S88
PMCID: PMC3287929  PMID: 22373521
4.  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.
doi:10.1158/1055-9965.EPI-09-1136
PMCID: PMC2838211  PMID: 20200424
familial esophageal adenocarcinomas; complex segregation analysis; dominant major gene inheritance; polygenic component; likelihood; AIC; unified model
5.  Comparison of a unified analysis approach for family and unrelated samples with the transmission-disequilibrium test to study associations of hypertension in the Framingham Heart Study 
BMC Proceedings  2009;3(Suppl 7):S22.
Population stratification is one of the major causes of spurious associations in association studies. A unified association approach based on principal-component analysis can overcome the effect of population stratification, as well as make use of both family and unrelated samples combined to increase power (family-case-control, or FamCC). In this study, we compared FamCC and the transmission-disequilibrium test (TDT) using data on hypertension, systolic blood pressure, and diastolic blood pressure in the Framingham Heart Study. Our study indicated FamCC has reasonable type I error for both the unrelated sample and the family sample for all three traits. For these three traits, we found results from FamCC were inconsistent with those from the TDT. We discuss the reasons for this inconsistency. After correcting for multiple tests, we did not detect any significant single-nucleotide polymorphisms by either FamCC or the TDT.
PMCID: PMC2795919  PMID: 20018012

Résultats 1-5 (5)