High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.

Chromosome 17q11-q21 is a region of the genome likely to harbor susceptibility to autism (MIM(209850)) based on earlier evidence of linkage to the disorder. This linkage is specific to multiplex pedigrees containing only male probands (MO) within the Autism Genetic Resource Exchange (AGRE). Earlier, Stone et al.(1) completed a high-density single nucleotide polymorphism association study of 13.7 Mb within this interval, but common variant association was not sufficient to account for the linkage signal. Here, we extend this single nucleotide polymorphism-based association study to complete the coverage of the two-LOD support interval around the chromosome 17q linkage peak by testing the majority of common alleles in 284 MO trios. Markers within an interval containing the gene, CACNA1G, were found to be associated with Autism Spectrum Disorder at a locally significant level (P=1.9 × 10(-5)). While establishing CACNA1G as a novel candidate gene for autism, these alleles do not contribute a sufficient genetic effect to explain the observed linkage, indicating that there is substantial genetic heterogeneity despite the clear linkage signal. The region thus likely harbors a combination of multiple common and rare alleles contributing to the genetic risk. These data, along with earlier studies of chromosomes 5 and 7q3, suggest few if any major common risk alleles account for Autism Spectrum Disorder risk under major linkage peaks in the AGRE sample. This provides important evidence for strategies to identify Autism Spectrum Disorder genes, suggesting that they should focus on identifying rare variants and common variants of small effect

‘My favourite things to do’ and ‘my favourite people’: Exploring salient aspects of children’s self-concept

This study explores the potential of the ‘draw-and-write’ method for inviting children to communicate salient aspects of their self-concept. Irish primary school children aged 10–13 years drew and wrote about their favourite people and things to do (social and active self). Children drew and described many salient activities (39 in total) and people – including pets. Results suggest that widely used, adult-constructed self-esteem scales for children, while multidimensional, are limited, and that ‘draw-and-write’ is an effective multimodal method with which children can express their social and active self-concepts

Soft believers and hard unbelievers in the Xhosa cattle-killing

A substantial minority, perhaps 15 per cent of all Xhosa, refused to obey the prophetess Nongqawuse's orders to kill their cattle and destroy their corn. This divided Xhosaland into two parties, the amathamba (‘soft’ ones, or believers) and the amagogotya (‘hard’ ones, or unbelievers). The affiliation of individuals was partly determined by a number of factors – lungsickness in cattle, political attitude towards the Cape Colony, religious beliefs, kinship, age and gender – but a systematic analysis of each of these factors in turn suggests that none of them was sufficiently important to constitute the basis of either party. The key to understanding the division lies in an analysis of the indigenous Xhosa terms ‘soft’ and ‘hard’. ‘Softness’ in Xhosa denotes the submissiveness of the individual to the common will of the community, whereas ‘hardness’ denotes the determination of the individual to pursue his own ends, even at communal expense. Translated into social terms, the ‘soft’ believers were those who remained committed to the mutual aid ethic of the declining precolonial society, whereas the ‘hard’ unbelievers were those who sought to seize advantage of the new opportunities offered by the colonial presence to increase their wealth and social prominence. The conflict between the social and personal imperatives was well expressed by Chief Smith Mhala, the unbelieving son of a believing father, when he said, ‘They say I am killing my father – so I would kill him before I would kill my cattle.’ Certainly, the division between amathamba and amagogotya ran much deeper than the division between belief and unbelief, and the Xhosa, in conferring these names, seem to have recognized the fact

The central beliefs of the Xhosa cattle-killing

The Xhosa cattle-killing movement of 1856–7 cannot be explained as a superstitious ‘pagan reaction’ to the intrusion of colonial rule and Christian civilization. It owes its peculiar form to the lungsickness epidemic of 1854, which carried off over 100,000 Xhosa cattle. The Xhosa theory of disease indicated that the sick cattle had been contaminated by the witchcraft practices of the people, and that these tainted cattle would have to be slaughtered lest they infect the pure new cattle which were about to rise. The idea of the resurrection of the dead was partly due to the Xhosa belief that the dead do not really die or depart from the world of the living, and partly to the Xhosa myth of creation, which held that all life originated in a certain cavern in the ground which might yet again pour forth its blessings on the earth. Christian doctrines, transmitted through the prophets Nxele and Mhlakaza, supplemented and elaborated these indigenous Xhosa beliefs. The Xhosa and the Christian elements united together in the person of the expected redeemer Sifuba-sibanzi (the broad-chested one). The central beliefs of the Xhosa cattle-killing were neither irrational nor atavistic. Ironically, it was probably because they were so rational and so appropriate that they ultimately proved to be so deadly

On several families of elliptic curves with arbitrary large Selmer groups

In this paper, we calculate the $\phi (\hat{\phi})-$Selmer groups S^{(\phi)} (E / \Q) and S^{(\hat{\varphi})} (E^{\prime} / \Q) of elliptic curves $y^{2} = x (x + \epsilon p D) (x + \epsilon q D)$ via descent theory (see [S, Chapter X]), in particular, we obtain that the Selmer groups of several families of such elliptic curves can be arbitrary large.Comment: 22 page

Association of the HLA locus and TNF with type I autoimmune hepatitis susceptibility in New Zealand Caucasians

PURPOSE: The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. METHODS: 77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. RESULTS: Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR = 2.45, 95% CI 1.65-3.61, p < 0.0001), rs3749971 (OR = 1.89, 95% CI 1.21-2.94, p = 0.004) and rs1800629 (OR = 2.06, 95% CI 1.41-3.01, p = 0.0001). Multivariate analysis showed that rs2187668 was independently associated with type 1 AIH susceptibility (OR = 2.40, 95% CI 1.46-3.93, p = 0.001). The C allele of FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR = 2.03, 95% CI 1.05-3.93, p = 0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR = 3.94, 95% CI 1.62-9.54, p = 0.0015). CONCLUSIONS: This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype

Dioctahedral mixed K-Na-micas and paragonite in diagenetic to low-temperature metamorphic terrains: bulk rock chemical, thermodynamic and textural constraints

Abstract Metamorphic mineral assemblages in low-temperature metaclastic rocks often contain paragonite and/or its precursor metastable phase (mixed K-Na-white mica). Relationships between the bulk rock major element chemistries and the formation of paragonite at seven localities from Central and SE-Europe were studied, comparing the bulk chemical characteristics with mineral assemblage, mineral chemical and metamorphic petrological data. Considerable overlaps between the projection fields of bulk chemistries of the Pg-free and Pg-bearing metaclastic rocks indicate significant differences between the actual (as analyzed) and effective bulk chemical compositions. Where inherited, clastic, inert phases/constituents were excluded, it was found that a decrease in Na/(Na+Al*) and in K/(K+Al*) ratios of rocks favors the formation and occurrence of Pg and its precursor phases (Al* denotes here the atomic quantity of aluminum in feldspars, white micas and “pure” hydrous or anhydrous aluminosilicates). In contrast to earlier suggestions, enrichment in Na and/or an increase in Na/K ratio by themselves do not lead to formation of paragonite. Bulk rock chemistries favorable to formation of paragonite and its precursor phases are characterized by enrichment in Al and depletion in Na, K, Ca (and also, Mg and Fe2+). Such bulk rock chemistries are characteristic of chemically “mature” (strongly weathered) source rocks of the pelites and may also be formed by synand post-sedimentary magmatism-related hydrothermal (leaching) activity. What part of the whole rock is active in determining the effective bulk chemistry was investigated by textural examination of diagenetic and anchizone-grade samples. It is hypothesized that although solid phases act as local sources and sinks, transport of elements such as Na through the grain boundaries have much larger communication distances. Sodium-rich white micas nucleate heterogeneously using existing phyllosilicates as templates and are distributed widely on the thin section scale. The results of modeling by THERMOCALC suggest that paragonite preferably forms at higher pressures in low-T metapelites. The stability fields of Pg-bearing assemblages increase, the Pg-in reaction line is shifted towards lower pressures, while the stability field of the Chl-Ms-Ab-Qtz assemblage decreases and is shifted towards higher temperatures with increasing Al* content and decreasing Na/(Na+Al*) and K/(K+Al*) ratios

PTPN22 R620W minor allele is a genetic risk factor for giant cell arteritis

Published online 7 April 2016.Giant cell arteritis (GCA) is one of the commonest forms of vasculitis in the elderly, and may result in blindness and stroke. The pathogenesis of GCA is not understood, although environmental, infectious and genetic risk factors are implicated. One gene of interest is PTPN22, encoding lymphoid protein tyrosine phosphatase (Lyp), expressed exclusively in immune cells, which is proposed to be an 'archetypal non-HLA autoimmunity gene'. The minor allele of a functional PTPN22 single nucleotide polymorphism (rs2476601, R620W), which disrupts an interaction motif in the protein, was originally reported to be associated with biopsy-proven GCA in Spanish patients, with supporting data from three replicate Northern European studies. Recently, this observation was extended with additional patients and controls, and studies encompassing European, Scandinavian, UK and American patients. The aim of our study was to determine the association between PTPN22 rs2476601 (R620W) and biopsy-proven GCA in an Australian case cohort.Susan Lester, Alex W Hewitt, Carlee D Ruediger, Linda Bradbury, Elisabeth De Smit, Michael D Wiese, Rachel Black, Andrew Harrison, Graeme Jones, Geoffrey O Littlejohn, Tony R Merriman, Bain Shenstone, Malcolm D Smith, Maureen Rischmueller, Matthew A Brown, Catherine L Hil

Finiteness Theorems for Binary Forms with Given Discriminant

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135212/1/plms0385.pd