Abstract
Background
Recent meta‐analyses of genome‐wide association studies (GWAS) have identified ∼30 susceptibility LOAD loci in addition to
APOE
, however the majority are common variants (minor ...allele frequency (MAF)>0.02). We used the dense, high‐resolution Haplotype Reference Consortium (HRC) r1.1 reference panel (64,976 haplotypes/39,235,157 SNPs), which allows imputation of rare variants (MAF>0.0008), to impute 44 GWAS datasets of the IGAP consortia to identify novel rare variant, gene, and pathway associations.
Method
We imputed 25,192 cases and 40,410 controls to the HRC r1.1 panel using Minimac3 on the Michigan Imputation Server. Converting imputed genotype probabilities to minor allele dosage, we ran logistic regression using SNPTEST on individual variants with MAF > 0.01 (and using generalized linear mixed models in R with family‐based datasets), and performed a fixed‐effects, inverse‐variance‐weighted meta‐analysis using METAL. Variants with MAF ≤ 0.01 were meta‐analyzed using score‐based tests via SeqMeta/R. Both analyses adjusted for age‐at‐onset(cases)/age‐at‐exam(controls), sex, and principal components for population substructure. Gene‐based associations were done with SKAT‐O and burden testing, while pathway associations were examined using VEGAS2.
Result
Discovery analyses of ∼39.2M genotyped or imputed SNVs confirmed single variant associations in 26 of 30 known IGAP LOAD loci at suggestive levels of significance (
P
< 10
−5
), with 12 known loci attaining genome‐wide statistical significance (
P
< 5 × 10
−8
) (Figure 1). Newly observed associations included common variants (MAF>0.01) in or near homologs of known AD loci,
EPHA5
(rs17086136, OR95% CI = 1.23 1.13,1.33,
P
= 6.36 × 10
−7
) and
ADAM28
(rs10096379, OR95% CI = 0.86 0.81,0.92,
P
= 3.02 × 10
−6
); in/near neuronal development genes including
DAB1
(neuronal migration; 1:57700874:T:G, OR95% CI = 0.71 0.62, 0.81,
P
= 6.94 × 10
−7
) and
DCC
(axon guidance; rs2054289, OR95% CI = 0.71 0.62, 0.83,
P
= 6.69 × 10
−6
); and in/near genes involved in cardiometabolic traits including
THADA
(type 2 diabetes; rs77101426, OR95% CI = 0.89 0.85, 0.95,
P
= 2.37 × 10
−6
). Several known AD loci demonstrated novel rare variant associations with genome‐wide significance, including
CR1
,
PICALM
, and the
MS4A
region (Figure 2), and novel rare variant associations were observed in or near genes involved in memory and cognitive function, including
HS3ST4
and
DBX1
. Independent replication in external datasets including the UK Biobank is on‐going.
Conclusion
Several novel LOAD candidate loci, including those with prior associations with neurodevelopment and cardiometabolic traits, were identified using high‐quality imputation of rare and low‐frequency variants in IGAP.
Background
Recent meta‐analyses of genome‐wide association studies (GWAS) have identified ∼30 susceptibility LOAD loci in addition to APOE, however the majority are common variants (minor allele ...frequency (MAF)>0.02). We used the dense, high‐resolution Haplotype Reference Consortium (HRC) r1.1 reference panel (64,976 haplotypes/39,235,157 SNPs), which allows imputation of rare variants (MAF>0.0008), to impute 44 GWAS datasets of the IGAP consortia to identify novel rare variant, gene, and pathway associations.
Method
We imputed 25,192 cases and 40,410 controls to the HRC r1.1 panel using Minimac3 on the Michigan Imputation Server. Converting imputed genotype probabilities to minor allele dosage, we ran logistic regression using SNPTEST on individual variants with MAF > 0.01 (and using generalized linear mixed models in R with family‐based datasets), and performed a fixed‐effects, inverse‐variance‐weighted meta‐analysis using METAL. Variants with MAF ≤ 0.01 were meta‐analyzed using score‐based tests via SeqMeta/R. Both analyses adjusted for age‐at‐onset(cases)/age‐at‐exam(controls), sex, and principal components for population substructure. Gene‐based associations were done with SKAT‐O and burden testing, while pathway associations were examined using VEGAS2.
Result
Discovery analyses of ∼39.2M genotyped or imputed SNVs confirmed single variant associations in 26 of 30 known IGAP LOAD loci at suggestive levels of significance (P < 10−5), with 12 known loci attaining genome‐wide statistical significance (P < 5 × 10−8) (Figure 1). Newly observed associations included common variants (MAF>0.01) in or near homologs of known AD loci, EPHA5 (rs17086136, OR95% CI = 1.23 1.13,1.33, P = 6.36 × 10−7) and ADAM28 (rs10096379, OR95% CI = 0.86 0.81,0.92, P = 3.02 × 10−6); in/near neuronal development genes including DAB1 (neuronal migration; 1:57700874:T:G, OR95% CI = 0.71 0.62, 0.81, P = 6.94 × 10−7) and DCC (axon guidance; rs2054289, OR95% CI = 0.71 0.62, 0.83, P = 6.69 × 10−6); and in/near genes involved in cardiometabolic traits including THADA (type 2 diabetes; rs77101426, OR95% CI = 0.89 0.85, 0.95, P = 2.37 × 10−6). Several known AD loci demonstrated novel rare variant associations with genome‐wide significance, including CR1, PICALM, and the MS4A region (Figure 2), and novel rare variant associations were observed in or near genes involved in memory and cognitive function, including HS3ST4 and DBX1. Independent replication in external datasets including the UK Biobank is on‐going.
Conclusion
Several novel LOAD candidate loci, including those with prior associations with neurodevelopment and cardiometabolic traits, were identified using high‐quality imputation of rare and low‐frequency variants in IGAP.
Application of nanotechnology in the agrifood system and the rising number of nanofood products on the market are creating concerns among consumers and other stakeholders. These concerns and other ...potential barriers to the commercialization of agrifood nanotechnology products may limit the ability to capture its full potential. Understanding the emerging trends and the links between underlying values, expressed attitudes, and actual behaviors involving consumer acceptance of agrifood nanotechnology is important for governance, risk regulation, and the achievement of the full potential of agrifood nanotechnology. The purpose of the study was to use systems mapping to examine and analyze critical links between consumer acceptance of agrifood nanotechnology and factors such as trust, stakeholders, institutions, knowledge, and human environmental health risks. The study used a meta-analysis of the risk perception literature and solicited the opinions of experts to develop the systems map. Factors affecting consumer acceptance of agrifood nanotechnology are dynamic, complex, interactive, and interdependent, and consumer decisions to accept agrifood nanotechnology were found to be the results of complex feedback structure. This study suggests several consumer policy and programmatic levels in the system toward enhancing consumer acceptance of agrifood nanotechnology products where warranted.
Let
F
be a field and
n
⩾
3
. Suppose
S
1
,
S
2
⊆
M
n
(
F
)
contain all rank-one idempotents. The structure of surjections
ϕ
:
S
1
→
S
2
satisfying
ABA
=
0
⇔
ϕ
(
A
)
ϕ
(
B
)
ϕ
(
A
)
=
0
is determined. ...Similar results are also obtained for (a) subsets of bounded operators acting on a complex or real Banach space
X
, (b) the space of Hermitian matrices acting on
n-dimensional vectors over a skew-field
D
, (c) subsets of self-adjoint bounded linear operators acting on an infinite dimensional complex Hilbert space. It is then illustrated that the results can be applied to characterize mappings
ϕ on matrices or operators such that
F
(
ABA
)
=
F
(
ϕ
(
A
)
ϕ
(
B
)
ϕ
(
A
)
)
for all
A
,
B
for functions
F such as the spectral norm, Schatten
p-norm, numerical radius and numerical range, etc.
Transmitting, splitting, and coupling of optical power are fundamental applications in photonics integrated circuits, which can be designed and fabricated on various material platforms. Material ...platforms characterized by high refractive index contrast allow higher integration of photonic devices into photonic integrated circuit, but mode field diameter of waveguides based on high refractive index material platform is more than 20 times smaller in comparison to mode field diameter of single mode optical fiber. This makes it more difficult coupling optical radiation from optical fiber to photonic integrated circuit. Current designs of optical couplers require complex technical and fabrication technology solutions with 100 nm resolution and less. Planar fiber to chip coupler, operating at wavelengths using in optical communication systems, based on enhancing surface plasmon polaritons requires for its production simple and more generally available technological steps operate with lower resolution. We report the design of plasmonic coupler and simulation of its properties by finite-difference time-domain (FDTD) simulation method.
The Gd–Ag–Al system Stel’makhovych, B.M; Zhak, O.V; Bilas, N.R ...
Journal of alloys and compounds,
01/2004, Letnik:
363, Številka:
1
Journal Article
Recenzirano
A systematic investigation of the interaction between the components in the Gd–Ag–Al system has been carried out and the phase diagram at 770 K has been constructed. The existence of the earlier ...known ternary compounds Gd
1.85Ag
8.2–9.4Al
8.8–7.6 (Th
2Ni
17-type structure), Gd
8Ag
20Al
46 (Yb
8Cu
17Al
49-type structure) and GdAg
2.2–2.8Al
2.8–2.2 (DyAg
2.4Al
2.6-type structure) has been confirmed and their homogeneity ranges have been established. Four new ternary compounds have been obtained: Gd
3Ag
2.0–2.8Al
9.0–8.2 (space group
Immm, La
3Al
11-type structure,
a=0.43306(3) nm,
b=1.26706(9) nm,
c=1.00145(7) nm,
R
I=0.090,
R
p=0.145), Gd
3Ag
2Al
7 (space group
R
3m
, Ca
3Cu
2Al
7-type structure,
a=0.55668(3) nm,
c=2.6382(2) nm,
R
I=0.076,
R
p=0.137), GdAg
0.8Al
1.2 (space group
Imma, KHg
2-type structure,
a=0.45899(6) nm,
b=0.72479(8) nm,
c=0.7889(1) nm,
R
I=0.083,
R
p=0.140) and ∼GdAg
3.5Al
1.5 (hexagonal symmetry,
a=0.5400(3) nm,
c=0.9268(5) nm).
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