Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways

An Evolutionary Framework for Association Testing in Resequencing Studies

Sequencing technologies are becoming cheap enough to apply to large numbers of study participants and promise to provide new insights into human phenotypes by bringing to light rare and previously unknown genetic variants. We develop a new framework for the analysis of sequence data that incorporates all of the major features of previously proposed approaches, including those focused on allele counts and allele burden, but is both more general and more powerful. We harness population genetic theory to provide prior information on effect sizes and to create a pooling strategy for information from rare variants. Our method, EMMPAT (Evolutionary Mixed Model for Pooled Association Testing), generates a single test per gene (substantially reducing multiple testing concerns), facilitates graphical summaries, and improves the interpretation of results by allowing calculation of attributable variance. Simulations show that, relative to previously used approaches, our method increases the power to detect genes that affect phenotype when natural selection has kept alleles with large effect sizes rare. We demonstrate our approach on a population-based re-sequencing study of association between serum triglycerides and variation in ANGPTL4

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan

Zooplankton response to flooding of a drought refuge and implications for the endangered fish species Craterocephalus fluviatilis cohabiting with alien Gambusia holbrooki

Disruption to a river's natural flow regime changes its ecological character, which becomes unfavourable for previously adapted biota. The zooplankton particularly are affected, and survival of larval and juvenile fish is largely determined by their availability. Alien fishes can also impact on recruitment in native fishes, sometimes through competition. In this regard, the invasive eastern Gambusia Gambusia holbrooki is linked to the decline of several fish species. It can have a substantial influence in shaping plankton communities, which implies that it competes with native fish that rely on the microfauna. The effects of river regulation and over abstraction of water in the Murray-Darling Basin, south-eastern Australia, were exacerbated by drought from 1997 to 2010. Consequently, the endangered Murray hardyhead Craterocephalus fluviatilis underwent substantial population decline and extirpations. The purpose of this study is to determine if a link exists between zooplankton response to flooding of a drought refuge and the recruitment success of C. fluviatilis in the presence of G. holbrooki. Flooding triggered sharp and substantial increases in the zooplankton and their eggs, which was the sole food of C. fluviatilis. This apparently benefitted the recruitment of C. fluviatilis, and sometimes alleviated diet overlap with G. holbrooki. Conversely, the zooplankton in a nearby non-flooded refuge was low in abundance and diversity, and all fish species were extirpated. The findings indicate that the flooding of drought refugia with relatively small volumes of water can be timed with ecological cues that would otherwise be desynchronized in highly regulated rivers, particularly during drought. © 2013 Springer Science+Business Media Dordrecht.Scotte D. Wedderburn, Karl A. Hillyard, Russell J. Shie