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Cosmic bounty hunter
\"Intergalactic bounty hunter Lobo has a new job. The evil aliens Kalibak and Desaad have hired him to capture Superman, dead or alive! However, when Lobo finally manages to wrangle up the Man of Steel, the aliens aren't far behind. They don't trust the ill-mannered bounty hunter, and quickly trap him beneath a force field with Superman. Lobo and the Man of Steel must set aside their differences in order to escape, capture the two villains, and collect the well-deserved reward.\"--T.p. verso.
Book
Architecture of the human regulatory network derived from ENCODE data
Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.
A description is given of the ENCODE consortium’s efforts to examine the principles of human transcriptional regulatory networks; the results are integrated with other genomic information to form a hierarchical meta-network where different levels have distinct properties.
ENCODE: architecture of the human regulatory network
This manuscript describes the effort of the ENCODE (Encyclopedia of DNA Elements) Consortium to examine the principles of human transcriptional regulatory networks, using a subset of 119 transcription factors. The results are integrated with other genomic information to form a multi-level meta-network in which different levels have distinct properties. The findings will aid future interpretations of human genomics and help us to understand the basic principles of human biology and disease.
Journal Article
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease
Gerard Schellenberg and colleagues report a genome-wide association study of late-onset Alzheimer's disease (LOAD), as part of the Alzheimer Disease Genetics Consortium. They identify common variants in
MS4A4/MS4A6E
,
CD2AP
,
CD33
and
EPHA1
associated with LOAD.
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at
MS4A4A
(rs4938933; stages 1 and 2, meta-analysis
P
(
P
M
) = 1.7 × 10
−9
, joint analysis
P
(
P
J
) = 1.7 × 10
−9
; stages 1, 2 and 3,
P
M
= 8.2 × 10
−12
),
CD2AP
(rs9349407; stages 1, 2 and 3,
P
M
= 8.6 × 10
−9
),
EPHA1
(rs11767557; stages 1, 2 and 3,
P
M
= 6.0 × 10
−10
) and
CD33
(rs3865444; stages 1, 2 and 3,
P
M
= 1.6 × 10
−9
). We also replicated previous associations at
CR1
(rs6701713;
P
M
= 4.6 × 10
−10
,
P
J
= 5.2 × 10
−11
),
CLU
(rs1532278;
P
M
= 8.3 × 10
−8
,
P
J
= 1.9 × 10
−8
),
BIN1
(rs7561528;
P
M
= 4.0 × 10
−14
,
P
J
= 5.2 × 10
−14
) and
PICALM
(rs561655;
P
M
= 7.0 × 10
−11
,
P
J
= 1.0 × 10
−10
), but not at
EXOC3L2
, to late-onset Alzheimer's disease susceptibility
1
,
2
,
3
.
Journal Article
Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer’s disease
Background
Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer’s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.
Results
We identify 13 loci with cross-population associations including known loci at/near
CR1
,
BIN1
,
TREM2
,
CD2AP
,
PTK2B
,
CLU
,
SHARPIN
,
MS4A6A
,
PICALM
,
ABCA7
,
APOE
, and two novel loci not previously reported at 11p12 (
LRRC4C
) and 12q24.13 (
LHX5-AS1
). We additionally identify three population-specific loci with genome-wide significance at/near
PTPRK
and
GRB14
in HIS and
KIAA0825
in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (
LRRC4C
,
LHX5-AS1
, and
PTPRK
) and insulin receptor activity regulation (
GRB14
).
Conclusions
Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near
LRRC4C
and
LHX5-AS1
, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the
SHARPIN
locus with only 13.7% of the sample size of the NHW GWAS study (
n
= 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer’s disease.
Journal Article
Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study (GWAS) of late-onset Alzheimer disease (LOAD) using a 3 stage design consisting of a discovery stage (Stage 1) and two replication stages (Stages 2 and 3). Both joint and meta-analysis analysis approaches were used. We obtained genome-wide significant results at MS4A4A [rs4938933; Stages 1+2, meta-analysis (PM) = 1.7 × 10−9, joint analysis (PJ) = 1.7 × 10−9; Stages 1–3, PM = 8.2 × 10−12], CD2AP (rs9349407; Stages 1–3, PM = 8.6 × 10−9), EPHA1 (rs11767557; Stages 1–3 PM = 6.0 × 10−10), and CD33 (rs3865444; Stages 1–3, PM = 1.6 × 10−9). We confirmed that CR1 (rs6701713; PM = 4.6×10−10, PJ = 5.2×10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9×10−8), BIN1 (rs7561528; PM = 4.0×10−14; PJ = 5.2×10−14), and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0×10−10) but not EXOC3L2 are LOAD risk loci1–3.
Journal Article