The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol

Purpose: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes. Patients and Methods: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects. Results: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0-18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17 x10(-9)) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54 x10(-8)). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3 x10(-5)), but not with rs116702638. Conclusion: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.Peer reviewe