Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Submarine canyons as the preferred habitat for wood-boring species of Xylophaga (Mollusca, Bivalvia)

13 páginas, 9 figuras, 5 tablas.Submarine canyons are often viewed as natural “debris concentrators” on the seafloor. Organic substrates may be more abundant inside than outside canyon walls. To determine the effects of the presence these substrates in the Blanes submarine canyon (NW Mediterranean) and its adjacent western open slope, we deployed wood to study colonizing organisms. Three replicate pine and oak cubes (i.e. most common trees inland) were moored at 900, 1200, 1500 and 1800 m depth and collected after 3, 9 and 12 months. Wood from inside the canyon was significantly more heavily colonized by the five morphotypes of wood-boring bivalves than was wood on the adjacent open slope. Xylophaga sp. A dominated all wood types and locations, with peak abundance at 900 and 1200 m depth. Its growth rate was highest (0.070 mm d−1) during the first three months and was faster (or it recruits earlier) in pine than in oak. Size distribution showed that several recruitment events may have occurred from summer to winter. Xylophaga sp. B, appeared first after 9 months and clearly preferred pine over oak. As the immersion time was the same, this strongly supported a specific association between recruiters and type of substrate. Three morphotypes, pooled as Xylophaga spp. C, were rare and seemed to colonize preferentially oak inside the canyon and pine in the adjacent open slope. Individuals of Xylophaga were more abundant inside the canyon than in nearby off-canyon locations. Blanes Canyon may serve as a long-term concentrator of land-derived vegetal fragments and as a consequence sustain more animals.The present work was developed within the framework of the projects PROMETEO (CTM2007-66316-C02-02/MAR) and DOSMARES (CTM2010-21810-C03-03).The study is also a contribution of C.R. and D.M. to the Consolidated Research Group 2009SRG655 of the “Generalitat de Catalunya”.Peer reviewe

Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual

Abstract Background Bone accrual impacts lifelong skeletal health, but genetic discovery has been primarily limited to cross-sectional study designs and hampered by uncertainty about target effector genes. Here, we capture this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans in a cohort of healthy children and adolescents, followed by genome-wide association studies (GWAS) and variant-to-gene mapping with functional follow-up. Results We identify 40 loci, 35 not previously reported, with various degrees of supportive evidence, half residing in topological associated domains harboring known bone genes. Of several loci potentially associated with later-life fracture risk, a candidate SNP lookup provides the most compelling evidence for rs11195210 (SMC3). Variant-to-gene mapping combining ATAC-seq to assay open chromatin with high-resolution promoter-focused Capture C identifies contacts between GWAS loci and nearby gene promoters. siRNA knockdown of gene expression supports the putative effector gene at three specific loci in two osteoblast cell models. Finally, using CRISPR-Cas9 genome editing, we confirm that the immediate genomic region harboring the putative causal SNP influences PRPF38A expression, a location which is predicted to coincide with a set of binding sites for relevant transcription factors. Conclusions Using a new longitudinal approach, we expand the number of genetic loci putatively associated with pediatric bone gain. Functional follow-up in appropriate cell models finds novel candidate genes impacting bone accrual. Our data also raise the possibility that the cell fate decision between osteogenic and adipogenic lineages is important in normal bone accrual.http://deepblue.lib.umich.edu/bitstream/2027.42/173859/1/13059_2020_Article_2207.pd

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk