Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.     

Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution

Surveys of protein-coding sequences for evidence of positive selection in humans or chimpanzees have flagged only a few genes known to function in neural or nutritional processes, despite pronounced differences between humans and chimpanzees in behavior, cognition and diet. It may be that most such differences are due to changes in gene regulation rather than protein structure. Here, we present the first survey of promoter (5'-flanking) regions, which are rich in cis-regulatory sequences, for evidence of positive selection in humans. Our results indicate that positive selection has targeted the regulation of many genes known to be involved in neural development and function, both in the brain and elsewhere in the nervous system, and in nutrition, particularly in glucose metabolism.     

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.     

In situ Os isotopes in abyssal peridotites bridge the isotopic gap between MORBs and their source mantle

Abyssal peridotites are assumed to represent the mantle residue of mid-ocean-ridge basalts (MORBs). However, the osmium isotopic compositions of abyssal peridotites and MORB do not appear to be in equilibrium, raising questions about the cogenetic relationship between those two reservoirs. However, the cause of this isotopic mismatch is mainly due to a drastic filtering of the data based on the possibility of osmium contamination by sea water. Here we present a detailed study of magmatic sulphides (the main carrier of osmium) in abyssal peridotites and show that the 187Os/188Os ratio of these sulphides is of primary mantle origin and can reach radiogenic values suggesting equilibrium with MORB. Thus, the effect of sea water on the osmium systematics of abyssal peridotites has been overestimated and consequently there is no true osmium isotopic gap between MORBs and abyssal peridotites.     

Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis

Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.     

Trend of of stature in France]

The average stature of 23,400 young adults was 172.33 cm in 1974; it is not the final size because they were 18 to 20 years old. Compared to previous data, we note that the rate of increase grows: it was of 0.3 cm every 10 years at the beginning of the century, of 1 cm in the middle of this century, actually it reaches 1.7 cm per ten years. Studying the correlations between the increase of stature and the variations of some factors during this century, we find multiple correlations accounting for the conditions of life, without a predominant factor. Among the sample of 1974, we find again the same result. The genetic factors (consanguinity, exogamy) show more modest correlations than mesological factors. The mental capacities show the strongest correlation, but does not explain the tendency occuring one in a hundred year. We still do not know why children grow quicker and reach a final bigger size than in the past.