Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24

Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer.     

Hereditary pancreatitis caused by triplication of the trypsinogen locus

Hereditary pancreatitis has been reported to be caused by 'gain-of-function' missense mutations in the cationic trypsinogen gene (PRSS1). Here we report the triplication of a approximately 605-kb segment containing the PRSS1 gene on chromosome 7 in five families with hereditary pancreatitis. This triplication, which seems to result in a gain of trypsin through a gene dosage effect, represents a previously unknown molecular mechanism causing hereditary pancreatitis.     

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.     

A 'dry' condensation origin for circumstellar carbonates

The signature of carbonate minerals has long been suspected in the mid-infrared spectra of various astrophysical environments such as protostars. Abiogenic carbonates are considered as indicators of aqueous mineral alteration in the presence of CO2-rich liquid water. The recent claimed detection of calcite associated with amorphous silicates in two planetary nebulae and protostars devoid of planetary bodies questions the relevance of this indicator; but in the absence of an alternative mode of formation under circumstellar conditions, this detection remains controversial. The main dust component observed in circumstellar envelopes is amorphous silicates, which are thought to have formed by non-equilibrium condensation. Here we report experiments demonstrating that carbonates can be formed with amorphous silicates during the non-equilibrium condensation of a silicate gas in a H2O-CO2-rich vapour. We propose that the observed astrophysical carbonates have condensed in H2O(g)-CO2(g)-rich, high-temperature and high-density regions such as evolved stellar winds, or those induced by grain sputtering upon shocks in protostellar outflows.     

A mechanism for impaired fear recognition after amygdala damage

Ten years ago, we reported that SM, a patient with rare bilateral amygdala damage, showed an intriguing impairment in her ability to recognize fear from facial expressions. Since then, the importance of the amygdala in processing information about facial emotions has been borne out by a number of lesion and functional imaging studies. Yet the mechanism by which amygdala damage compromises fear recognition has not been identified. Returning to patient SM, we now show that her impairment stems from an inability to make normal use of information from the eye region of faces when judging emotions, a defect we trace to a lack of spontaneous fixations on the eyes during free viewing of faces. Although SM fails to look normally at the eye region in all facial expressions, her selective impairment in recognizing fear is explained by the fact that the eyes are the most important feature for identifying this emotion. Notably, SM's recognition of fearful faces became entirely normal when she was instructed explicitly to look at the eyes. This finding provides a mechanism to explain the amygdala's role in fear recognition, and points to new approaches for the possible rehabilitation of patients with defective emotion perception.     

A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility

Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.     

Host plants influence parasitism of forest caterpillars

Patterns of association between herbivores and host plants have been thought to reflect the quality of plants as food resources as influenced by plant nutrient composition, defences, and phenology. Host-plant-specific enemies, that is, the third trophic level, might also influence the distribution of herbivores across plant species. However, studies of the evolution of herbivore host range have generally not examined the third trophic level, leaving unclear the importance of this factor in the evolution of plant-insect herbivore interactions. Analysis of parasitoid rearings by the Canadian Forest Insect Survey shows that parasitism of particular Lepidoptera species is strongly host-plant-dependent, that the pattern of host-plant dependence varies among species of caterpillars, and that some parasitoid species are themselves specialized with respect to tree species. Host-plant-dependent parasitism suggests the possibility of top-down influence on host plant use. Differences in parasitism among particular caterpillar-host plant combinations could select for specialization of host plant ranges within caterpillar communities. Such specialization would ultimately promote the species diversification of Lepidoptera in temperate forests with respect to escape from enemies.     

Evidence for synergism in steroid hormone-receptor association

Summary A number of glucocorticoids stimulated oestradiol binding to liver cytosol receptor; oestradiol activated glucocorticoid receptor association at a time when it reversed triamcinolone mediated increase in liver glycogen synthesis.These studies were supported by the DRGST (IMB 7570744), the INSERM (CL 7650014) and the CNRS (AI 03 1917).