Statistical Epistasis and Functional Brain Imaging Support a Role of Voltage-Gated Potassium Channels in Human Memory

Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed “missing heritability.” The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (Pnominal combined = 0.000001). The epistatic interaction was robust, as it was significant in a screening (Pnominal = 0.0000012) and in a replication sample (Pnominal = 0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (Pnominal = 0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits

Systematic quantification of gene interactions by phenotypic array analysis

A phenotypic array method, developed for quantifying cell growth, was applied to the haploid and homozygous diploid yeast deletion strain sets. A growth index was developed to screen for non-additive interacting effects between gene deletion and induced perturbations. From a genome screen for hydroxyurea (HU) chemical-genetic interactions, 298 haploid deletion strains were selected for further analysis. The strength of interactions was quantified using a wide range of HU concentrations affecting reference strain growth. The selectivity of interaction was determined by comparison with drugs targeting other cellular processes. Bio-modules were defined as gene clusters with shared strength and selectivity of interaction profiles. The functions and connectivity of modules involved in processes such as DNA repair, protein secretion and metabolic control were inferred from their respective gene composition. The work provides an example of, and a general experimental framework for, quantitative analysis of gene interaction networks that buffer cell growth

A Large-Scale Rheumatoid Arthritis Genetic Study Identifies Association at Chromosome 9q33.2

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (ORcommon = 1.28, trend Pcomb = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (Pcomb<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend Pcomb: 1.45E-06 → 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential

The origin and composition of carbonatite-derived carbonate-bearing fluorapatite deposits

Carbonate-bearing fluorapatite rocks occur at over 30 globally distributed carbonatite complexes and represent a substantial potential supply of phosphorus for the fertiliser industry. However, the process(es) involved in forming carbonate-bearing fluorapatite at some carbonatites remain equivocal, with both hydrothermal and weathering mechanisms inferred. In this contribution, we compare the paragenesis and trace element contents of carbonate-bearing fluorapatite rocks from the Kovdor, Sokli, Bukusu, Catalão I and Glenover carbonatites in order to further understand their origin, as well as to comment upon the concentration of elements that may be deleterious to fertiliser production. The paragenesis of apatite from each deposit is broadly equivalent, comprising residual magmatic grains overgrown by several different stages of carbonate-bearing fluorapatite. The first forms epitactic overgrowths on residual magmatic grains, followed by the formation of massive apatite which, in turn, is cross-cut by late euhedral and colloform apatite generations. Compositionally, the paragenetic sequence corresponds to a substantial decrease in the concentration of rare earth elements (REE), Sr, Na and Th, with an increase in U and Cd. The carbonate-bearing fluorapatite exhibits a negative Ce anomaly, attributed to oxic conditions in a surficial environment and, in combination with the textural and compositional commonality, supports a weathering origin for these rocks. Carbonate-bearing fluorapatite has Th contents which are several orders of magnitude lower than magmatic apatite grains, potentially making such apatite a more environmentally attractive feedstock for the fertiliser industry. Uranium and cadmium contents are higher in carbonate-bearing fluorapatite than magmatic carbonatite apatite, but are much lower than most marine phosphorites