Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Composição química, digestibilidade e cinética de degradação ruminal das silagens de híbridos de girassol em diferentes épocas de semeadura Effects of sowing dates on chemical composition, digestibility and ruminal degradation kinetics of silages from sunflower hybrids

Objetivou-se estimar o valor nutritivo das silagens de quatro híbridos de girassol - Rumbosol-91 (forrageiro), M-734 (duplo-propósito), C-11 (duplo-propósito) e BRS-191 (granífero) - semeados em três épocas: outubro (antecipada), novembro (normal) e dezembro (tardia) - por meio de análises químicas, da digestibilidade e da cinética de degradação ruminal. O delineamento experimental foi em blocos ao acaso, com arranjo fatorial 4 x 3 (quatro híbridos x três épocas de semeadura) e três repetições. Os teores de MS variaram de 23,2 a 43,0%; o pH, de 4,0 a 5,1; e o N-NH3%/NT, de 5,3 a 16,8%. Os teores de CZ oscilaram de 6,8 a 8,8% e aumentaram da semeadura em outubro para dezembro. O Rumbosol-91 apresentou teores menores de EE e maiores de N na parede celular, de N indisponível e de carboidratos totais (CHOT). Os teores de PB aumentaram e os de CHOT diminuíram de outubro para dezembro. A semeadura de novembro e o C-11 apresentaram menores teores de FDN, FDNcp e FDA. O C-11 semeado em novembro apresentou menor teor de LDA. A semeadura de outubro e o Rumbosol-91 tiveram maior proporção de LDA%/FDN. O Rumbosol-91 apresentou maior DIVMS e DIVFDN. A semeadura de novembro e os híbridos C-11 e M-734 apresentaram maior teor de NDT. O desaparecimento da MS pode ser representado por um único perfil de degradação. A proporção de FDN indegradável (I) aumentou da semeadura em outubro para dezembro, com maiores valores para o BRS-191 semeado em dezembro. A extensão (Vf1) e a taxa (k1) de degradação da fração solúvel de rápida digestão diminuíram da semeadura em outubro para dezembro, com maiores valores para o Rumbosol-91 semeado em outubro. A relação entre análise química, digestibilidade, NDT e cinética de degradação ruminal foi melhor para os híbridos M-734 e C-11 semeados em novembro.<br>The objective of this trial was to estimate chemical composition, digestibility and ruminal degradation kinetics of silages from four sunflower hybrids: Rumbosol-91 (forage), M-734 (double purpose), C-11 (double purpose) and BRS-191 (grain) sowed in October (early), November (normal) and December (late). A randomized complete block design in a 4 x 3 factorial arrangement (four hybrids x three seeding dates) with three replicates was used. Dry matter values ranged from 23.2 to 43.0%, pH from 4.0 to 5.1, and NH3-N%/TN from 5.3 to 16.8%. Ash values increased from October to December ranging from 6.8 to 8.8%. The Rumbosol-91 showed the lowest content of EE and the highest contents of N in the cell wall, unavailable N and total carbohydrates (TC). Crude protein contents increased from October to December while the opposite was observed for TC. November sowing and the C-11 gave the lowest contents of NDF, NDFcp and ADF. The C-11 sowed in November gave the lowest ADL values. October sowing and the Rumbosol-91 gave the highest content of ADL%/NDF. The Rumbosol-91 gave higher IVDMD and IVNDFD. November sowing and the C-11 and M-734 hybrids gave the highest value of TDN. Only one degradation profile was necessary to fit DM disappearance data. The proportion of undegradable NDF (I) increased from October to December sowing, being the BRS-191 sowed in December gave the highest values. The extent (Vf1) and rate (k1) of degradation of soluble fractions of rapid digestion decreased from October to December sowing, being the Rumbosol-91 sowed in October gave the highest values. The overall nutritive value measured by chemical composition, digestibility, total digestible nutrients and ruminal degradation kinetics was better for the M-734 and C-11 hybrids sowed in November