120 research outputs found
A meta-analysis of genome-wide association studies of growth differentiation Factor-15 concentration in blood
Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the“COPI-mediated anterograde transport” gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels
Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning
Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes
Observations of the High Redshift Universe
(Abridged) In these lectures aimed for non-specialists, I review progress in
understanding how galaxies form and evolve. Both the star formation history and
assembly of stellar mass can be empirically traced from redshifts z~6 to the
present, but how the various distant populations inter-relate and how stellar
assembly is regulated by feedback and environmental processes remains unclear.
I also discuss how these studies are being extended to locate and characterize
the earlier sources beyond z~6. Did early star-forming galaxies contribute
significantly to the reionization process and over what period did this occur?
Neither theory nor observations are well-developed in this frontier topic but
the first results presented here provide important guidance on how we will use
more powerful future facilities.Comment: To appear in `First Light in Universe', Saas-Fee Advanced Course 36,
Swiss Soc. Astrophys. Astron. in press. 115 pages, 64 figures (see
http://www.astro.caltech.edu/~rse/saas-fee.pdf for hi-res figs.) For lecture
ppt files see
http://obswww.unige.ch/saas-fee/preannouncement/course_pres/overview_f.htm
The Theory of Brown Dwarfs and Extrasolar Giant Planets
Straddling the traditional realms of the planets and the stars, objects below
the edge of the main sequence have such unique properties, and are being
discovered in such quantities, that one can rightly claim that a new field at
the interface of planetary science and and astronomy is being born. In this
review, we explore the essential elements of the theory of brown dwarfs and
giant planets, as well as of the new spectroscopic classes L and T. To this
end, we describe their evolution, spectra, atmospheric compositions, chemistry,
physics, and nuclear phases and explain the basic systematics of
substellar-mass objects across three orders of magnitude in both mass and age
and a factor of 30 in effective temperature. Moreover, we discuss the
distinctive features of those extrasolar giant planets that are irradiated by a
central primary, in particular their reflection spectra, albedos, and transits.
Aspects of the latest theory of Jupiter and Saturn are also presented.
Throughout, we highlight the effects of condensates, clouds, molecular
abundances, and molecular/atomic opacities in brown dwarf and giant planet
atmospheres and summarize the resulting spectral diagnostics. Where possible,
the theory is put in its current observational context.Comment: 67 pages (including 36 figures), RMP RevTeX LaTeX, accepted for
publication in the Reviews of Modern Physics. 30 figures are color. Most of
the figures are in GIF format to reduce the overall size. The full version
with figures can also be found at:
http://jupiter.as.arizona.edu/~burrows/papers/rm
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
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele
Mouse Chromosome 11
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46996/1/335_2004_Article_BF00648429.pd
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