Genome-wide linkage scan for loci influencing plasma triglycerides

Background: Plasma triglyceride concentration is known to be a significant risk factor for cardiovascular disease (CVD). Previous studies have found that the level of triglycerides is strongly influenced by genetic factors. Methods: To identify quantitative trait loci influencing triglycerides, we conducted a genome-wide linkage scan on data from 485 Australian adult dizygotic twin pairs. Prior to linkage analysis, triglyceride values were adjusted for the effects of covariates including age, sex, time since last meal, time of blood collection (CT) and time to plasma separation. Results: The heritability estimate for ln(triglyceride) adjusted for all above fixed effects was 0.49. The highest multipoint LOD score observed was 2.94 (genome-wide p=0.049) on chromosome 7 (at 65cM). This 7p region contains several candidate genes. Two other regions with suggestive multipoint LOD scores were also identified on chromosome 4 (LOD score=2.26 at 62cM) and chromosome X (LOD score=2.01 at 81cM). Conclusions: The linkage peaks found represent newly identified regions for more detailed study, in particular the significant linkage observed on chromosome 7p13. \ (c) 2006 Elsevier B.V. All rights reserved.

Evolving genetic regulatory networks using an artificial genome

Boolean models of genetic regulatory networks (GRNs) have been shown to exhibit many of the characteristic dynamics of real GRNs, with gene expression patterns settling to point attractors or limit cycles, or displaying chaotic behaviour, depending upon the connectivity of the network and the relative proportions of excitatory and inhibitory interactions. This range of behaviours is only apparent, however, when the nodes of the GRN are updated synchronously, a biologically implausible state of affairs. In this paper we demonstrate that evolution can produce GRNs with interesting dynamics under an asynchronous update scheme. We use an Artificial Genome to generate networks which exhibit limit cycle dynamics when updated synchronously, but collapse to a point attractor when updated asynchronously. Using a hill climbing algorithm the networks are then evolved using a fitness function which rewards patterns of gene expression which revisit as many previously seen states as possible. The final networks exhibit “fuzzy limit cycle” dynamics when updated asynchronously.

Dynamics of gene expression in an artificial genome

Complex systems techniques provide a powerful tool to study the emergent properties of networks of interacting genes. In this study we extract models of genetic regulatory networks from an artificial genome, represented by a sequence of nucleotides, and analyse how variations in the connectivity and degree of inhibition of the extracted networks affects the resulting classes of behaviours. For low connectivity systems were found to be very stable. Only with higher connectivity was a significant occurrence of chaos found. Most interestingly, the peak in occurrence of chaos occurs perched on the edge of a phase transition in the occurrence of attractors.

Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic

In a genome-wide RNA-mediated interference screen for genes required in membrane traffic - including endocytic uptake, recycling from endosomes to the plasma membrane, and secretion - we identified 168 candidate endocytosis regulators and 100 candidate secretion regulators. Many of these candidates are highly conserved among metazoans but have not been previously implicated in these processes. Among the positives from the screen, we identified PAR-3, PAR-6, PKC-3 and CDC-42, proteins that are well known for their importance in the generation of embryonic and epithelial-cell polarity. Further analysis showed that endocytic transport in Caenorhabditis elegans coelomocytes and human HeLa cells was also compromised after perturbation of CDC-42/Cdc42 or PAR-6/Par6 function, indicating a general requirement for these proteins in regulating endocytic traffic. Consistent with these results, we found that tagged CDC-42/Cdc42 is enriched on recycling endosomes in C. elegans and mammalian cells, suggesting a direct function in the regulation of transport.

The Human Genome Project: its relevance to ocular disease

This article describes the history of the Human Genome Project, how the human genome was sequenced, and analyses the likely impact which the results will have on the diagnosis, scientific understanding and, ultimately, treatment of ocular disease in the future.

Genome-wide screening for DNA variants associated with reading and language traits

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome-wide association scan (GWAS) meta-analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P≈10 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills. Genome-wide association scan meta-analysis for reading and language ability. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank

Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.

A Case-Only Genome-wide Association Study of Gender- and Age-specific Risk Markers for Childhood Leukemia

Males and age group 1 to 5 years show a much higher risk for childhood acute lymphoblastic leukemia (ALL). We performed a case-only genome-wide association study (GWAS), using the Illumina Infinium HumanCoreExome Chip, to unmask gender- and age-specific risk variants in 240 non-Hispanic white children with ALL recruited at Texas Children’s Cancer Center, Houston, Texas. Besides statistically most significant results, we also considered results that yielded the highest effect sizes. Existing experimental data and bioinformatic predictions were used to complement results, and to examine the biological significance of statistical results. Our study identified novel risk variants for childhood ALL. The SNP, rs4813720 (RASSF2), showed the statistically most significant gender-specific associations (P < 2 x 10-6). Likewise, rs10505918 (SOX5) yielded the lowest P value (P < 1 x 10-5) for age-specific associations, and also showed the statistically most significant association with age-at-onset (P < 1 x 10-4). Two SNPs, rs12722042 and 12722039, from the HLA-DQA1 region yielded the highest effect sizes (odds ratio (OR) = 15.7; P = 0.002) for gender-specific results, and the SNP, rs17109582 (OR = 12.5; P = 0.006), showed the highest effect size for age-specific results. Sex chromosome variants did not appear to be involved in gender-specific associations. The HLA-DQA1 SNPs belong to DQA1*01:07and confirmed previously reported male-specific association with DQA1*01:07. Twenty one of the SNPs identified as risk markers for gender- or age-specific associations were located in the transcription factor binding sites and 56 SNPs were non-synonymous variants, likely to alter protein function. Although bioinformatic analysis did not implicate a particular mechanism for gender- and age-specific associations, RASSF2 has an estrogen receptor-alpha binding site in its promoter. The unknown mechanisms may be due to lack of interest in gender- and age-specificity in associations. These results provide a foundation for further studies to examine the gender- and age-differential in childhood ALL risk. Following replication and mechanistic studies, risk factors for one gender or age group may have a potential to be used as biomarkers for targeted intervention for prevention and maybe also for treatment.