Identity by descent and association analysis of dichotomous traits based on large pedigrees

The goals of our analysis were to map functional loci, which contribute to the case-control status of a trait of interest, using large pedigrees. We used logistic regression fitted with the generalized estimation equation to test associations between a dichotomous phenotype and all genotyped common and rare single-nucleotide polymorphisms. In addition to the association study, we also developed and applied a simple and fast identical-by-descent-based test to identify loci that were shared among affected individuals more often than expected by chance. Among the top significant loci, we assessed the statistical power and the false discovery rate of both methods. We also demonstrated that family-based studies, compared with the standard population-based association studies, have great values and advantages for the discovery of multiple rare causal variants

A comparison between microsatellite and single-nucleotide polymorphism markers with respect to two measures of information content

Using the Genetic Analysis Workshop 14 (GAW14) simulated dataset, we compare microsatellite and single-nucleotide polymorphism (SNP) markers in terms of two measures of information content, the traditional entropy-based information content measure, and a new "relative information" measure. Both attempt to measure the amount of information contained in the markers about the identity-by-descent (IBD) sharing among relatives. The performance of the two information measures are compared based on their variability and ability to predict change in the LOD score (ΔLOD) as map density increases for SNP markers. Although in a linked region, LOD scores are correlated with measures of information, we observe that none of the measures predict the LOD score itself very well. In an unlinked region, the LOD score is not related to either measures of information. The information content of microsatellite markers with 7.5-cM spacing is slightly higher than that of SNP markers with 3-cM spacing. At these map densities, microsatellites are found to be uniformly more informative than SNPs irrespective of their level of heterozygosity. For SNPs, we found that as the level of heterozygosity increases, the information content increases. As reported in all other previous studies, we also found that high-density SNPs have higher information content compared to low-density microsatellites. Performance of both the two information measures considered here are similar, but the relative information measure predicts ΔLOD as marker density increases better than the traditional entropy-based information measure

Pathway-based analysis using reduced gene subsets in genome-wide association studies

<p>Abstract</p> <p>Background</p> <p>Single Nucleotide Polymorphism (SNP) analysis only captures a small proportion of associated genetic variants in Genome-Wide Association Studies (GWAS) partly due to small marginal effects. Pathway level analysis incorporating prior biological information offers another way to analyze GWAS's of complex diseases, and promises to reveal the mechanisms leading to complex diseases. Biologically defined pathways are typically comprised of numerous genes. If only a subset of genes in the pathways is associated with disease then a joint analysis including all individual genes would result in a loss of power. To address this issue, we propose a pathway-based method that allows us to test for joint effects by using a pre-selected gene subset. In the proposed approach, each gene is considered as the basic unit, which reduces the number of genetic variants considered and hence reduces the degrees of freedom in the joint analysis. The proposed approach also can be used to investigate the joint effect of several genes in a candidate gene study.</p> <p>Results</p> <p>We applied this new method to a published GWAS of psoriasis and identified 6 biologically plausible pathways, after adjustment for multiple testing. The pathways identified in our analysis overlap with those reported in previous studies. Further, using simulations across a range of gene numbers and effect sizes, we demonstrate that the proposed approach enjoys higher power than several other approaches to detect associated pathways.</p> <p>Conclusions</p> <p>The proposed method could increase the power to discover susceptibility pathways and to identify associated genes using GWAS. In our analysis of genome-wide psoriasis data, we have identified a number of relevant pathways for psoriasis.</p

The heritability of subjective cognitive complaints in older Australian twins

Background Subjective cognitive complaints (SCCs) may be a precursor to mild cognitive impairment (MCI) and dementia. This study aimed to examine the heritability of SCCs, and the influence of personality and mood on the relationship between SCCs and memory performance. Method The heritability of SCCs were examined in 306 twin pairs using structural equation modelling. Genetic, environmental, and phenotypic correlations between SCCs and memory performance, personality, and mood scores were determined. Result SCCs were low to moderately heritable. Mood appeared to be related to SCCs by an environmental correlation, whereas memory performance was related to SCCs by a genetic correlation. SCCs had a significant amount of both genetic and environmental variances not explained by memory performance, personality, or mood. Conclusion Our results suggest that SCCs are influenced both by a person’s mood and their memory performance, and that these determinants are not mutually exclusive. Much of the genetic and environmental components to SCCs were specific to SCCs, with the specific factors yet to be determined

The Heritability of Subjective Cognitive Complaints in Older Australian Twins.

Background: Subjective cognitive complaints (SCCs) may be a precursor to mild cognitive impairment (MCI) and dementia. Objective: This study aimed to examine the heritability of SCCs, correlations between SCCs and memory ability, and the influence of personality and mood on these relationships. Methods: Participants were 306 twin pairs. The heritability of SCCs and the genetic correlations between SCCs and memory performance, personality, and mood scores were determined using structural equation modelling. Results: SCCs were low to moderately heritable. Memory performance, personality and mood were genetically, environmentally, and phenotypically correlated with SCCs in bivariate analysis. However, in multivariate analysis, only mood and memory performance had significant correlations with SCCs. Mood appeared to be related to SCCs by an environmental correlation, whereas memory performance was related to SCCs by a genetic correlation. The link between personality and SCCs was mediated by mood. SCCs had a significant amount of both genetic and environmental variances not explained by memory performance, personality, or mood. Conclusion: Our results suggest that SCCs are influenced both by a person’s mood and their memory performance, and that these determinants are not mutually exclusive. While SCCs had genetic overlap with memory performance and environmental association with mood, much of the genetic and environmental components that comprised SCCs were specific to SCCs, though these specific factors are yet to be determined

Nature Versus Nurture – Studying the Relationships Between Diet and Depression in Older Adults

Abstract Objectives Prior work suggests that higher fruit and vegetable consumption may protect against depression in older adults. By better understanding the influence of genetic and environmental factors on fruit and vegetable intakes, more effective interventions could be designed to increase intakes in older adults to reduce and/or assist with the treatment of depression in older adults. The aim of this heritability study is to estimate the genetic and environmental influences on the consumption of fruit and vegetables in older adults and to investigate if there are shared influences between fruit and vegetable intakes and depression. Methods Participants (n = 374 twins, 67.1% female; 208 identical; 166 non-identical, ≥ 65-years) were drawn from the Older Australian Twins Study. Data on diet (validated food frequency questionnaire) and depressive symptoms (15-item Geriatric Depression Scale) were collected. The contribution of genetic and environmental influences on fruit and vegetable intake were estimated by comparing identical and non-identical twin intakes using structural equation modelling. A trivariate model was used to estimate the genetic and environmental correlation between total fruit and vegetable intakes and depression. Results In this study, vegetable intake was moderately influenced by genetics (heritability = 36%) with the remaining 64% due to the unique environment. Heritability was highest for brassica vegetables (40%), while intake of starchy vegetables was not heritable. Genetics did not significantly influence the intake of fruit. No significant genetic or environmental correlations were detected between fruit or vegetable intakes and depression. The number of participants meeting Australian Dietary Guidelines for fruit and vegetable intake was low (fruit 46.5%; vegetables 2.9%). Conclusions Consumption of vegetables, particularly bitter tasting brassica vegetables, was significantly influenced by genetics. These findings provide novel insights into the drivers of fruit and vegetable consumption in older adults and may help shape interventions to increase intakes, with the view of reducing the burden of depression. Funding Sources The Older Australian Twins Study was funded by the National Health & Medical Research Council and Australian Research Council

Molecular analysis of CHX10 and MFRP in Chinese subjects with primary angle closure glaucoma and short axial length eyes

Molecular Vision141313-131

Changes in the plasma proteome at asymptomatic and symptomatic stages of autosomal dominant Alzheimer\u27s disease

The autosomal dominant form of Alzheimer\u27s disease (ADAD) is far less prevalent than late onset Alzheimer\u27s disease (LOAD), but enables well-informed prospective studies, since symptom onset is near certain and age of onset is predictable. Our aim was to discover plasma proteins associated with early AD pathology by investigating plasma protein changes at the asymptomatic and symptomatic stages of ADAD. Eighty-one proteins were compared across asymptomatic mutation carriers (aMC, n = 15), symptomatic mutation carriers (sMC, n = 8) and related noncarriers (NC, n = 12). Proteins were also tested for associations with cognitive measures, brain amyloid deposition and glucose metabolism. Fewer changes were observed at the asymptomatic than symptomatic stage with seven and 16 proteins altered significantly in aMC and sMC, respectively. This included complement components C3, C5, C6, apolipoproteins A-I, A-IV, C-I and M, histidine-rich glycoprotein, heparin cofactor II and attractin, which are involved in inflammation, lipid metabolism and vascular health. Proteins involved in lipid metabolism differed only at the symptomatic stage, whereas changes in inflammation and vascular health were evident at asymptomatic and symptomatic stages. Due to increasing evidence supporting the usefulness of ADAD as a model for LOAD, these proteins warrant further investigation into their potential association with early stages of LOAD