Collapsing-based and kernel-based single-gene analyses applied to Genetic Analysis Workshop 17 mini-exome data

Recently there has been great interest in identifying rare variants associated with common diseases. We apply several collapsing-based and kernel-based single-gene association tests to Genetic Analysis Workshop 17 (GAW17) rare variant association data with unrelated individuals without knowledge of the simulation model. We also implement modified versions of these methods using additional information, such as minor allele frequency (MAF) and functional annotation. For each of four given traits provided in GAW17, we use the Bayesian mixed-effects model to estimate the phenotypic variance explained by the given environmental and genotypic data and to infer an individual-specific genetic effect to use directly in single-gene association tests. After obtaining information on the GAW17 simulation model, we compare the performance of all methods and examine the top genes identified by those methods. We find that collapsing-based methods with weights based on MAFs are sensitive to the “lower MAF, larger effect size” assumption, whereas kernel-based methods are more robust when this assumption is violated. In addition, many false-positive genes identified by multiple methods often contain variants with exactly the same genotype distribution as the causal variants used in the simulation model. When the sample size is much smaller than the number of rare variants, it is more likely that causal and noncausal variants will share the same or similar genotype distribution. This likely contributes to the low power and large number of false-positive results of all methods in detecting causal variants associated with disease in the GAW17 data set

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

A unified framework for multi-locus association analysis of both common and rare variants

<p>Abstract</p> <p>Background</p> <p>Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers.</p> <p>Results</p> <p>We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication.</p> <p>Conclusions</p> <p>We identified a single risk haplotype with a directionally consistent effect in both samples in the gene <it>GAK</it>, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes <it>SYN3 </it>and <it>NGLY1</it>, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.</p

Association of Toll-like receptor 4 (TLR4) with chronic plaque type psoriasis and psoriatic arthritis.

Family studies have provided overwhelming evidence for an underlying genetic component to psoriasis. Toll-like receptors (TLRs) are key transmembrane proteins in both the innate and adaptive immune responses which are known to be integral processes in psoriasis. Recent functional studies support this notion having suggested a role for TLR4 in the pathogenesis of psoriasis. Furthermore a missense polymorphism in the TLR4 gene has been associated with a number of autoimmune conditions, including Crohn diseases, making TLR4 a viable candidate gene for investigation. The aim of this study was to investigate polymorphisms across the TLR4 region with a high-density single nucleotide polymorphism (SNP) panel in a large cohort of patients with chronic plaque type psoriasis. Twenty SNPs were successfully genotyped using Sequenom iPLEX Gold platform in 2826 UK chronic plaque type psoriasis patients including subgroup data on presence of confirmed psoriatic arthritis (n = 1839) and early-onset psoriasis (n = 1466) was available. Allele frequencies for psoriasis patients were compared against imputed Wellcome Trust Case Control Consortium controls (n = 4861). Significant association was observed between a missense variant rs4986790 of TLR4 (Asp229Gly) and plaque type psoriasis (p = 2 × 10(-4)) which was also notable in those with psoriatic arthritis (p = 2 × 10(-4)) and early-onset psoriasis (p = 8 × 10(-4)). We present data suggestive of an association between a functional variant and an intronic variant of TLR4 and chronic plaque type psoriasis and psoriatic arthritis. However, validation of this association in independent cohorts will be necessary

Molecular Structures of Quiescently Grown and Brain-Derived Polymorphic Fibrils of the Alzheimer Amyloid Aβ9-40 Peptide: A Comparison to Agitated Fibrils

The presence of amyloid deposits consisting primarily of Amyloid-β (Aβ) fibril in the brain is a hallmark of Alzheimer's disease (AD). The morphologies of these fibrils are exquisitely sensitive to environmental conditions. Using molecular dynamics simulations combined with data from previously published solid-state NMR experiments, we propose the first atomically detailed structures of two asymmetric polymorphs of the Aβ9-40 peptide fibril. The first corresponds to synthetic fibrils grown under quiescent conditions and the second to fibrils derived from AD patients' brain-extracts. Our core structure in both fibril structures consists of a layered structure in which three cross-β subunits are arranged in six tightly stacked β-sheet layers with an antiparallel hydrophobic-hydrophobic and an antiparallel polar-polar interface. The synthetic and brain-derived structures differ primarily in the side-chain orientation of one β-strand. The presence of a large and continually exposed hydrophobic surface (buried in the symmetric agitated Aβ fibrils) may account for the higher toxicity of the asymmetric fibrils. Our model explains the effects of external perturbations on the fibril lateral architecture as well as the fibrillogenesis inhibiting action of amphiphilic molecules

Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study

Introduction: Radiation exposure at a young age is one of the strongest risk factors for breast cancer. Germline mutations in genes involved in the DNA-damage repair pathway (DDRP) may render women more susceptible to radiation-induced breast cancer. Methods: We evaluated the contribution of germline mutations in the DDRP genes BRCA1, BRCA2, CHEK2 and ATM to the risk of radiation-induced contralateral breast cancer (CBC). The germline mutation frequency was assessed, in a case-only study, in women who developed a CBC after they had a first breast cancer diagnosed before the age of 50 years, and who were (n = 169) or were not (n = 78) treated with radiotherapy for their first breast tumour. Results: We identified 27 BRCA1, 5 BRCA2, 15 CHEK2 and 4 truncating ATM germline mutation carriers among all CBC patients tested (21%). The mutation frequency was 24.3% among CBC patients with a history of radiotherapy, and 12.8% among patients not irradiated for the first breast tumour (odds ratio 2.18 (95% confidence interval 1.03 to 4.62); p = 0.043). The association between DDRP germline mutation carriers and risk of radiation-induced CBC seemed to be strongest in women who developed their second primary breast tumour at least 5 years after radiotherapy. Th

Iron and zinc content of selected foods in the diet of schoolchildren in Kumi district, east of Uganda: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Iron and zinc are essential micronutrients for humans and deficiency of the two elements is widespread in the world with the highest prevalence in less developed countries. There are few data on dietary intake of iron and zinc in Uganda, and no food composition table is available. There is hardly any widely published literature that clearly documents the quality of Ugandan children's diet. Thus information of both food intake and the concentration of these trace elements in local food ingredients are needed in order to assess daily intake.</p> <p>Methods</p> <p>The present study focused on the iron and zinc content in selected foods and intake of the micronutrients iron and zinc among schoolchildren in Kumi District, Uganda. Over a period of 4 weeks single 24-hour dietary recall interviews were carried out on a convenience sample of 178 schoolchildren (9-15 years old). Data from the dietary recalls was used when selecting foods for chemical analysis.</p> <p>Results</p> <p>Results from this study showed that the iron concentrations varied, and were high in some cereals and vegetables. The zinc concentrations in foods generally corresponded with results from other African countries (Mali and Kenya). Data from the 24-hour dietary recall showed that the daily Recommended Nutrient Intake (RNI) was met for iron but not for zinc.</p> <p>Conclusions</p> <p>The schoolchildren of Kumi district had a predominantly vegetable based diet. Foods of animal origin were consumed occasionally. The iron content in the selected foods was high and variable, and higher than in similar ingredients from Kenya and Mali, while the zinc concentrations were generally in accordance with reported values. The total daily zinc (mg) intake does not meet the daily RNI. The iron intake is adequate according to RNI, but due to iron contamination and reduced bioavailability, RNI may not be met in a vegetable based diet. More studies are needed to investigate possible sources of contamination.</p

Multiple interactions between the alpha2C- and beta1-adrenergic receptors influence heart failure survival

<p>Abstract</p> <p>Background</p> <p>Persistent stimulation of cardiac β₁-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α_2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (<it>ADRB1 </it>and <it>ADRA2C</it>, respectively) on the risk of death/transplant in heart failure patients.</p> <p>Methods</p> <p>Sixteen sequence variations in <it>ADRA2C </it>and 17 sequence variations in <it>ADRB1 </it>were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation.</p> <p>Results</p> <p>Three polymorphisms in <it>ADRA2C </it>and five polymorphisms in <it>ADRB1 </it>were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18) relative to all other genotype classes.</p> <p>Conclusion</p> <p>Multiple polymorphisms act synergistically between the <it>ADRA2C </it>and <it>ADRB1 </it>genes to increase risk of death or cardiac transplant in heart failure patients.</p