Predictive factors of manual dexterity and cognitive performance at 17 years: a 10-year longitudinal study in a rural area of France.

Studies of predictive factors of manual dexterity in adolescents and young adults are lacking. The present longitudinal study reports the relationship between cognitive and behavioural assessments at age 7 years and the schooling, cognitive performance, and manual dexterity at age 17 years. The participants were 65 schoolchildren, 30 boys and 35 girls, from a rural area in France. Assessment at age 7 years included the McCarthy scales and questionnaires measuring the behavior of the child, completed by the mother, the teacher, and the assessing psychologist. Assessment at age 17 years included schooling situation (whether they were in high school or not), cognitive testing (WAIS-R, Trail Making, Verbal Fluency, Cancel H, Stroop, Memory Assessment Scales), and manual dexterity testing (dynamometer, Finger Tapping, Santa Ana Test, Purdue Pegboard). After controlling for effects of parental education and IQ, a negative teachers' rating of children's behaviour and abilities in first-grade (7 years) was correlated with early cessation of schooling, but also, unexpectedly, with higher scores for manual dexterity at 17 years. Manual dexterity was not related to cognitive performance at 17 years. It is suggested that the relationship between manual and cognitive performance varies during development. Although manual exploratory behaviour is an important correlate of early cognitive development, manual dexterity is probably not related to later academic performance.

CKM and LILRB5 are associated with serum levels of creatine kinase.

BACKGROUND: Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs for the treatment and prevention of cardiovascular disease. Creatine kinase (CK) is a commonly used biomarker to assist in the diagnosis of statin-induced myotoxicity but the normal range of CK concentrations is wide, which limits its use as a diagnostic biomarker. METHODS AND RESULTS: We conducted a genome-wide association study of serum CK levels in 3412 statin users. Patients were recruited in Quebec, Canada, and genotyped on Illumina Human610-Quad and an iSelect panel enriched for lipid homeostasis, hypertension, and drug metabolism genes. We found a strong association signal between serum levels of CK and the muscle CK (CKM) gene (rs11559024: P=3.69×10(-16); R(2)=0.02) and with the leukocyte immunoglobulin-like receptor subfamily B member 5 (LILRB5) gene (rs2361797: P=1.96×10(-10); R(2)=0.01). Genetic variants in those 2 genes were independently associated with CK levels in statin users. Results were successfully replicated in 5330 participants from the Montreal Heart Institute Biobank in statin users for CKM (rs11559024: P=4.32×10(-16); R(2)=0.02) and LILRB5 (rs12975366 P=4.45×10(-10); R(2)=0.01) and statin nonusers (P=4.08×10(-7), R(2)=0.01; P=3.17×10(-9), R(2)=0.02, respectively). CONCLUSIONS: This is the first genome-wide study to report on the underlying genetic determinants of CK variation in a population of statin users. We found statistically significant association for variants in the CKM and LILRB5 genes.

Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians.

BACKGROUND: Familial history is a strong risk factor for coronary artery disease (CAD), especially for early-onset myocardial infarction (MI). Several genes and chromosomal regions have been implicated in the genetic cause of coronary artery disease/MI, mostly through the discovery of familial mutations implicated in hyper-/hypocholesterolemia by linkage studies and single nucleotide polymorphisms by genome-wide association studies. Except for a few examples (eg, PCSK9), the role of low-frequency genetic variation (minor allele frequency [MAF]) ≈0.1%-5% on MI/coronary artery disease predisposition has not been extensively investigated. METHODS AND RESULTS: We selected 68 candidate genes and sequenced their exons (394 kb) in 500 early-onset MI cases and 500 matched controls, all of French-Canadian ancestry, using solution-based capture in pools of nonindexed DNA samples. In these regions, we identified 1852 single nucleotide variants (695 novel) and captured 85% of the variants with MAF≥1% found by the 1000 Genomes Project in Europe-ancestry individuals. Using gene-based association testing, we prioritized for follow-up 29 low-frequency variants in 8 genes and attempted to genotype them for replication in 1594 MI cases and 2988 controls from 2 French-Canadian panels. Our pilot association analysis of low-frequency variants in 68 candidate genes did not identify genes with large effect on MI risk in French Canadians. CONCLUSIONS: We have optimized a strategy, applicable to all complex diseases and traits, to discover efficiently and cost-effectively DNA sequence variants in large populations. Resequencing endeavors to find low-frequency variants implicated in common human diseases are likely to require very large sample size.

Génome Québec & Montreal Heart Institute Pharmacogenomics Centre: a translational pharmacogenomics platform--from R&D to the clinic.

The Génome Québec and Montreal Heart Institute Pharmacogenomics Centre (Montreal, Canada), created in 2006, is a translational pharmacogenomics platform whose main objectives are to conduct pharmacogenomics research, provide pharmacogenomics services to the academic, biotechnology and pharmaceutical sectors, and integrate pharmacogenomics solutions into the healthcare system. The Centre has brought together a multidisciplinary team of researchers with expertise in genomics, bioinformatics and clinical trial research. All the Centre's clinical research studies are supported by the Centre's unique Good Laboratory Practice facility framework, which has the ability to perform pharmaceutical clinical trials and deliver clinical diagnostics under the highest standards. The Centre has successfully leveraged its experience and expertise in technology development and pharmacogenomics clinical trial work to attract funding and collaborative partnerships in both the public and private sectors.

Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.