Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards

10.1186/2040-2392-5-7Molecular Autism51

Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10−11). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10−10) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss

Western Bumble Bee: Declines in the Continental United States and Range-Wide Information Gaps

In recent decades, many bumble bee species have declined due to changes in habitat, climate, and pressures from pathogens, pesticides, and introduced species. The western bumble bee (Bombus occidentalis), once common throughout western North America, is a species of concern and will be considered for listing by the U.S. Fish and Wildlife Service (USFWS) under the Endangered Species Act (ESA). We attempt to improve alignment of data collection and research with USFWS needs to consider redundancy, resiliency, and representation in the upcoming species status assessment. We reviewed existing data and literature on B. occidentalis, highlighting information gaps and priority topics for research. Priorities include increased knowledge of trends, basic information on several life‐history stages, and improved understanding of the relative and interacting effects of stressors on population trends, especially the effects of pathogens, pesticides, climate change, and habitat loss. An understanding of how and where geographic range extent has changed for the two subspecies of B. occidentalis is also needed. We outline data that could be easily collected in other research projects that would increase their utility for understanding range‐wide trends of bumble bees. We modeled the overall trend in occupancy from 1998 to 2018 of Bombus occidentalis within the continental United States using existing data. The probability of local occupancy declined by 93% over 21 yr from 0.81 (95% CRI = 0.43, 0.98) in 1998 to 0.06 (95% CRI = 0.02, 0.16) in 2018. The decline in occupancy varied spatially by landcover and other environmental factors. Detection rates vary in both space and time, but peak detection across the continental United States occurs in mid‐July. We found considerable spatial gaps in recent sampling, with limited sampling in many regions, including most of Alaska, northwestern Canada, and the southwestern United States. We therefore propose a sampling design to address these gaps to best inform the ESA species status assessment through improved assessment of how the spatial distribution of stressors influences occupancy changes. Finally, we request involvement via data sharing, participation in occupancy sampling with repeated visits to distributed survey sites, and complementary research to address priorities outlined in this paper

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC- PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European- American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta- analysis and we do not replicate previously reported associations. Still, SNP- level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci

Wide-field CO isotopologue emission and the CO-to-H2_2 factor across the nearby spiral galaxy M101

Carbon monoxide (CO) emission is the most widely used tracer of the bulk molecular gas in the interstellar medium (ISM) in extragalactic studies. The CO-to-H$_2$ conversion factor, $\alpha_{\rm CO}$, links the observed CO emission to the total molecular gas mass. However, no single prescription perfectly describes the variation of $\alpha_{\rm CO}$ across all environments across galaxies as a function of metallicity, molecular gas opacity, line excitation, and other factors. Using resolved spectral line observations of CO and its isotopologues, we can constrain the molecular gas conditions and link them to a variation in the conversion factor. We present new IRAM 30-m 1mm and 3mm line observations of $^{12}$CO, $^{13}$CO, and C$^{18}$O} across the nearby galaxy M101. Based on the CO isotopologue line ratios, we find that selective nucleosynthesis and opacity changes are the main drivers of the variation in the line emission across the galaxy. Furthermore, we estimated $\alpha_{\rm CO(1-0)}$ using different approaches, including (i) the dust mass surface density derived from far-IR emission as an independent tracer of the total gas surface density and (ii) LTE-based measurements using the optically thin $^{13}$CO(1-0) intensity. We find an average value of $\alpha_{\rm CO}=4.4{\pm}0.9\rm\,M_\odot\,pc^{-2}(K\,km\,s^{-1})^{-1}$ across the galaxy, with a decrease by a factor of 10 toward the 2 kpc central region. In contrast, we find LTE-based values are lower by a factor of 2-3 across the disk relative to the dust-based result. Accounting for $\alpha_{\rm CO}$ variations, we found significantly reduced molecular gas depletion time by a factor 10 in the galaxy's center. In conclusion, our result suggests implications for commonly derived scaling relations, such as an underestimation of the slope of the Kennicutt Schmidt law, if $\alpha_{\rm CO}$ variations are not accounted for.Comment: Accepted for publication in A&A, 25 pages, 15 figure

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans

Introduction The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown. Methods To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans. Results Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value <0.05), including cg13301722 on chromosome 7, which lies between the genes SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans. Discussion Taken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P &lt; 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T&gt;C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P &lt; .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies