Linkage analysis of alcoholism-related electrophysiological phenotypes: genome scans with microsatellites compared to single-nucleotide polymorphisms

P300 amplitude is an electrophysiological quantitative trait that is correlated with both alcoholism and smoking status. Using the Collaborative Study on the Genetics of Alcoholism data, we performed model-free linkage analysis to investigate the relationship between alcoholism, P300 amplitude, and habitual smoking. We also analyzed the effect of parent-of-origin on alcoholism, and utilized both microsatellites (MS) markers and single-nucleotide polymorphisms (SNPs). We found significant evidence of linkage for alcoholism to chromosome 10; inclusion of P300 amplitude as a covariate provided additional evidence of linkage to chromosome 12. This same region on chromosome 12 showed some evidence for a parent-of-origin effect. We found evidence of linkage for the P300 phenotype to chromosome 7 in non-smokers, and to chromosome 17 in alcoholics. The effects of alcoholism and habitual smoking on P300 amplitude appear to have separate genetic determinants. Overall, there were few differences between MS and SNP genome scans. The use of covariates and parent-of-origin effects allowed detection of linkage not seen otherwise

Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia

<p>Abstract</p> <p>Background</p> <p>In utero interactions between incompatible maternal and fetal genotypes are a potential mechanism for the onset or progression of pregnancy related diseases such as pre-eclampsia (PE). However, the optimal analytical approach and study design for evaluating incompatible maternal/offspring genotype combinations is unclear.</p> <p>Methods</p> <p>Using simulation, we estimated the type I error and power of incompatible maternal/offspring genotype models for two analytical approaches: logistic regression used with case-control mother/offspring pairs and the log-linear regression used with case-parent triads. We evaluated a real dataset consisting of maternal/offspring pairs with and without PE for incompatibility effects using the optimal analysis based on the results of the simulation study.</p> <p>Results</p> <p>We identified a single coding scheme for the incompatibility effect that was equally or more powerful than all of the alternative analysis models evaluated, regardless of the true underlying model for the incompatibility effect. In addition, the log-linear regression was more powerful than the logistic regression when the heritability was low, and more robust to adjustment for maternal or fetal effects. For the PE data, this analysis revealed three genes, lymphotoxin alpha (<it>LTA</it>), von Willebrand factor (<it>VWF</it>), and alpha 2 chain of type IV collagen (<it>COL4A2</it>) with possible incompatibility effects.</p> <p>Conclusion</p> <p>The incompatibility model should be evaluated for complications of pregnancy, such as PE, where the genotypes of two individuals may contribute to the presence of disease.</p

Effect of genotyping error in model-free linkage analysis using microsatellite or single-nucleotide polymorphism marker maps

Errors while genotyping are inevitable and can reduce the power to detect linkage. However, does genotyping error have the same impact on linkage results for single-nucleotide polymorphism (SNP) and microsatellite (MS) marker maps? To evaluate this question we detected genotyping errors that are consistent with Mendelian inheritance using large changes in multipoint identity-by-descent sharing in neighboring markers. Only a small fraction of Mendelian consistent errors were detectable (e.g., 18% of MS and 2.4% of SNP genotyping errors). More SNP genotyping errors are Mendelian consistent compared to MS genotyping errors, so genotyping error may have a greater impact on linkage results using SNP marker maps. We also evaluated the effect of genotyping error on the power and type I error rate using simulated nuclear families with missing parents under 0, 0.14, and 2.8% genotyping error rates. In the presence of genotyping error, we found that the power to detect a true linkage signal was greater for SNP (75%) than MS (67%) marker maps, although there were also slightly more false-positive signals using SNP marker maps (5 compared with 3 for MS). Finally, we evaluated the usefulness of accounting for genotyping error in the SNP data using a likelihood-based approach, which restores some of the power that is lost when genotyping error is introduced

Schistosomal hepatic fibrosis and the interferon gamma receptor: a linkage analysis using single-nucleotide polymorphic markers

A minority of individuals infected with the parasite Schistosoma mansoni develops hepatic fibrosis. HLA studies in Egypt and a candidate gene search in a Sudanese population indicate that the host&apos;s genetics contribute to disease susceptibility. In an Egyptian community, 32.7% of individuals 11 years and older had significant fibrosis by WHO ultrasound criteria. Linkage to 10 candidate genes was tested using 89 affected sibling pairs from 40 pedigrees in this community. The candidates included genes that initiate fibrosis, participate in collagen synthesis, or control collagen degradation. Two to four single-nucleotide polymorphisms (SNPs) were genotyped per locus, and 188 individuals were genotyped at 48 markers. Model-free modified Haseman-Elston analysis identified linkage to a SNP in the interferon gamma receptor locus (P ¼ 0.000001). There was also weak evidence for linkage to the interleukin 13-4 region and tissue growth factor beta 1

Identification of nephropathy candidate genes by comparing sclerosis-prone and sclerosis-resistant mouse strain kidney transcriptomes

Abstract Background The genetic architecture responsible for chronic kidney disease (CKD) remains incompletely described. The Oligosyndactyly (Os) mouse models focal and segmental glomerulosclerosis (FSGS), which is associated with reduced nephron number caused by the Os mutation. The Os mutation leads to FSGS in multiple strains including the ROP-Os/+. However, on the C57Bl/6J background the mutation does not cause FSGS, although nephron number in these mice are equivalent to those in ROP-Os/+ mice. We exploited this phenotypic variation to identify genes that potentially contribute to glomerulosclerosis. Methods To identify such novel genes, which regulate susceptibility or resistance to renal disease progression, we generated and compared the renal transcriptomes using serial analysis of gene expression (SAGE) from the sclerosis-prone ROP-Os/+ and sclerosis resistant C57-Os/+ mouse kidneys. We confirmed the validity of the differential gene expression using multiple approaches. We also used an Ingenuity Pathway Analysis engine to assemble differentially regulated molecular networks. Cell culture techniques were employed to confirm functional relevance of selected genes. Results A comparative analysis of the kidney transcriptomes revealed multiple genes, with expression levels that were statistically different. These novel, candidate, renal disease susceptibility/resistance genes included neuropilin2 (Nrp2), glutathione-S-transferase theta (Gstt1) and itchy (Itch). Of 34 genes with the most robust statistical difference in expression levels between ROP-Os/+ and C57-Os/+ mice, 13 and 3 transcripts localized to glomerular and tubulointerstitial compartments, respectively, from micro-dissected human FSGS biopsies. Network analysis of all significantly differentially expressed genes identified 13 connectivity networks. The most highly scored network highlighted the roles for oxidative stress and mitochondrial dysfunction pathways. Functional analyses of these networks provided evidence for activation of transforming growth factor beta (TGFβ) signaling in ROP-Os/+ kidneys despite similar expression of the TGFβ ligand between the tested strains. Conclusions These data demonstrate the complex dysregulation of normal cellular functions in this animal model of FSGS and suggest that therapies directed at multiple levels will be needed to effectively treat human kidney diseases.http://deepblue.lib.umich.edu/bitstream/2027.42/112491/1/12882_2011_Article_362.pd

Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study

Background: Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM. Methods We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. Results: Among 12 500 women (mean age &#x003D; 60 years, range &#x003D; 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR &#x003D; 1.40, 95% CI &#x003D; 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR &#x003D; 1.49, 95% CI &#x003D; 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR &#x003D; 4.12, 95% CI &#x003D; 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR &#x003D; 7.19, 95% CI &#x003D; 5.00 to 10.35). Conclusions: Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety

Patients' ratings of genetic conditions validate a taxonomy to simplify decisions about preconception carrier screening via genome sequencing

Advances in genome sequencing and gene discovery have created opportunities to efficiently assess more genetic conditions than ever before. Given the large number of conditions that can be screened, the implementation of expanded carrier screening using genome sequencing will require practical methods of simplifying decisions about the conditions for which patients want to be screened. One method to simplify decision making is to generate a taxonomy based on expert judgment. However, expert perceptions of condition attributes used to classify these conditions may differ from those used by patients. To understand whether expert and patient perceptions differ, we asked women who had received preconception genetic carrier screening in the last 3 years to fill out a survey to rate the attributes (predictability, controllability, visibility, and severity) of several autosomal recessive or X-linked genetic conditions. These conditions were classified into one of five taxonomy categories developed by subject experts (significantly shortened lifespan, serious medical problems, mild medical problems, unpredictable medical outcomes, and adult-onset conditions). A total of 193 women provided 739 usable ratings across 20 conditions. The mean ratings and correlations demonstrated that participants made distinctions across both attributes and categories. Aggregated mean attribute ratings across categories demonstrated logical consistency between the key features of each attribute and category, although participants perceived little difference between the mild and serious categories. This study provides empirical evidence for the validity of our proposed taxonomy, which will simplify patient decisions for results they would like to receive from preconception carrier screening via genome sequencing

Generating a taxonomy for genetic conditions relevant to reproductive planning

As genome or exome sequencing (hereafter genome-scale sequencing) becomes more integrated into standard care, carrier testing is an important possible application. Carrier testing using genome-scale sequencing can identify a large number of conditions, but choosing which conditions/genes to evaluate as well as which results to disclose can be complicated. Carrier testing generally occurs in the context of reproductive decision-making and involves patient values in a way that other types of genetic testing may not. The Kaiser Permanente Clinical Sequencing Exploratory Research program is conducting a randomized clinical trial of preconception carrier testing that allows participants to select their preferences for results from among broad descriptive categories rather than selecting individual conditions. This paper describes 1) the criteria developed by the research team, the return of results committee (RORC), and stakeholders for defining the categories; 2) the process of refining the categories based on input from patient focus groups and validation through a patient survey; and, 3) how the RORC then assigned specific gene-condition pairs to taxonomy categories being piloted in the trial. The development of four categories (serious, moderate/mild, unpredictable, late onset) for sharing results allows patients to select results based on their values without separately deciding their interest in knowing their carrier status for hundreds of conditions. A fifth category, lifespan limiting, was always shared. The lessons learned may be applicable in other results disclosure situations, such as incidental findings