| 1. |
|
|
| 2. |
|
|
| 3. |
- Weiner, D. J., et al.
(författare)
-
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
-
Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
|
|
| 4. |
- Anney, R. J. L., et al.
(författare)
-
Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
- 2017
-
Ingår i: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) < 1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P= 9 x10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental- related genes such as EXT1, ASTN2, MACROD2, and HDAC4.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Paul, Dirk S., et al.
(författare)
-
Increased DNA methylation variability in type 1 diabetes across three immune effector cell types
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
|
|
| 10. |
|
|
| 11. |
- Naeraa, Tomas, et al.
(författare)
-
A lower crustal mafic source for the ca. 2550 Ma Qorqut Granite Complex in southern West Greenland
- 2014
-
Ingår i: Lithos. - : Elsevier BV. - 0024-4937 .- 1872-6143. ; 192, s. 291-304
-
Tidskriftsartikel (refereegranskat)abstract
- The late Neoarchaean Qorqut Granite Complex is the youngest large igneous intrusion in the Nuuk region in southern West Greenland, where basement is primarily of Eoarchaean and Mesoarchaean age with a tonalite-trondhjemite-granodiorite (TTG) composition. The Qorqut granite is generally undeformed and it intruded during a prolonged period, starting at ca. 2730 Ma, characterised by crustal reworking, possibly related to syn- or post accretion tectonics or continental collision. We present major and trace element whole rock chemistry and combined U/Pb, Hf and O isotope data from zircon. We obtained a mean zircon U/Pb age of 2547 +/- 4 Ma (MSWD = 0.63). Initial sHf values range from - 12 to -18 requiring a long residence time and a rather homogeneous source. Sample averaged zircon delta O-18 values range from 6.1 +/- 0.2%. to 6.5 +/- 0.3/0.7%o best interpreted with a source region of mainly unweathered mantle derived igneous rocks. Compared to the regional TTG basement, the QGC is characterised by low CaO and Na2O and high K2O, LREE and Rb contents, and a stronger fractionated REE pattern with a negative Eu anomaly. We show that the homogeneous Hf isotope signature of the granite together with its low epsilon value and its pristine oxygen isotope composition are best explained with an Eoarchaean mafic source with a Lu-176/Hf-176 around 0.015-0.019. Trace element modelling confirms that a mafic source in REE and with an eclogitic residue and with plagioclase as a fractionating phase would generate appropriate melt compositions. Modelling requires residual rutile in the source which constrain the pressures to > ca. 13-18 kbar. Zirconium saturation temperatures suggest magma temperatures in the range 750-850 degrees C. The obtained P-T conditions suggest a lower crustal source region in a thickened crustal unit consistent with a post or late continental collisional setting. (C) 2014 Elsevier B.V. All rights reserved.
|
|
| 12. |
|
|
