Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

The selective conversion of biomass derived coumalic acid to functionalized aromatics and novel intermediates

The heavy reliance on petroleum as the raw feedstock for the production of chemicals imparts negative environmental effects and exerts economic pressure due to the diminishing availability of natural crude oil reserves. A change in the raw material supply can already be observed in the U.S., where petroleum is increasingly being replaced by inexpensive shale gas. The increased shale gas dependence, however, reduces the availability of >C4 chemicals (e.g. aromatics). Since existing alternatives, such as selectively accessing aromatics from renewable carbon sources (e.g. biomass), are still facing significant limitations, there is a need to develop new technologies. An innovative approach to selectively access bio-based aromatics in high yield is provided herein via a Diels-Alder/decarboxylation/palladium catalyzed dehydrogenation domino sequence starting from coumalic acid (or methyl coumalate) in conjunction with the inexpensive and easy to separate/recycle ethylene (or propylene). This approach is guided by an in-depth reaction network analysis, solvent and kinetic studies, and complemented by density functional theory (DFT) calculations with the goal of providing key insights into the formation of intermediates and by-products on the pathway to aromatics. The solvent studies show that polar aprotic solvents including 1,4-dioxane, y-valerolactone and acetone lead to excellent aromatic yield and selectivity (78 - 91 mol%) when starting with coumalic acid, whereas non-polar toluene provides only poor solubility of coumalic acid which is associated with by-product formation and, therefore, poor aromatic yield ( The kinetic analysis of relevant steps reveals that decarboxylation is the rate limiting step, which is in agreement with DFT calculations. This critical information enables the development of a tailored catalyst through which significant process optimizations are achieved, including the selective access to dihydrobenzenes from bicyclic lactones in high yield (> 98 mol%). Novel dihydrobenzene structures have interesting dual functionality and further expand the diverse coumalate platform with species that are challenging to access via conventional petroleum routes. Further diversification of bicyclic lactones is achieved through the choice of solvent and catalyst (e.g. Brà ¸nsted and Lewis acids) by enabling highly selective pathway modifications. Lewis acids enhance decarboxylation, whereas Brà ¸nsted acids enable ring-opening of bicyclic lactones to produce novel chemical species. Ring-opening is also achieved when bicyclic lactone conversion is mediated in methanol, a polar protic solvent. Cleavage of the lactone bridge is, thereby, induced through methanolysis in the absence of a Brà ¸nsted acid, therefore providing another environmentally benign pathway. Lastly, the combination of kinetic studies, DFT calculations and high resolution magic angle spinning NMR characterization reveals important insights into the Lewis acid (y-Al2O3) catalyzed decarboxylation mechanism at the solvent-catalyst-interface and provides evidence of the catalytic active site responsible for decarboxylation. This knowledge can be broadly transferred for decarboxylation of a range of 2-pyrone derived bicyclic lactones and improve access to novel dihydrobenzenes and aromatics from biomass.</p

Paired electrocatalytic hydrogenation and oxidation of 5-(hydroxymethyl)furfural for efficient production of biomass-derived monomers

Electrochemical conversion of biomass-derived compounds is a promising route for sustainable chemical production. Herein, we report unprecedentedly high efficiency for conversion of 5-(hydroxymethyl)furfural (HMF) to biobased monomers by pairing HMF reduction and oxidation half-reactions in one electrochemical cell. Electrocatalytic hydrogenation of HMF to 2,5-bis(hydroxymethyl)furan (BHMF) was achieved under mild conditions using carbon-supported Ag nanoparticles (Ag/C) as the cathode catalyst. The competition between Ag-catalyzed HMF hydrogenation to BHMF and undesired HMF hydrodimerization and hydrogen evolution reactions was sensitive to cathode potential. Also, the carbon support material in Ag/C was active for HMF reduction at strongly cathodic potentials, leading to additional hydrodimerization and low BHMF selectivity. Accordingly, precise control of the cathode potential was implemented to achieve high BHMF selectivity and efficiency. In contrast, the selectivity of HMF oxidation facilitated by a homogeneous electrocatalyst, 4-acetamido-TEMPO (ACT, TEMPO = 2,2,6,6-tetramethylpiperidine-1-oxyl), together with an inexpensive carbon felt electrode, was insensitive to anode potential. Thus, it was feasible to conduct HMF hydrogenation to BHMF and oxidation to 2,5-furandicarboxylic acid (FDCA) in a single divided cell operated under cathode potential control. Electrocatalytic HMF conversion in the paired cell achieved high yields of BHMF and FDCA (85% and 98%, respectively) and a combined electron efficiency of 187%, corresponding to a nearly two-fold enhancement compared to the unpaired cells.This article is published as Chadderdon, Xiaotong H., David J. Chadderdon, Toni Pfennig, Brent H. Shanks, and Wenzhen Li. "Paired electrocatalytic hydrogenation and oxidation of 5-(hydroxymethyl) furfural for efficient production of biomass-derived monomers." Green Chemistry 21, no. 22 (2019): 6210-6219. DOI: 10.1039/C9GC02264C. Posted with permission.</p

cis,cis-Muconic acid isomerization and catalytic conversion to biobased cyclic-C6-1,4-diacid monomers

Renewable terephthalic and 1,4-cyclohexanedicarboxylic acids can be produced from biomass via muconic acid using a combination of biological and chemical processes. In this conversion scheme, cis,cis-mucononic acid is first obtained by fermentation using either sugar or lignin monomers as a feedstock. The diunsaturated cis,cis-diacid is then isomerized to trans,trans-muconic acid, reacted with biobased ethylene through Diels–Alder cycloaddition, and further hydrogenated or dehydrogenated to yield the desired 100% renewable cyclic dicarboxylic acid. The isomerization of cis,cis- to trans,trans-muconic acid represents the main bottleneck in this process due to undesired side reactions that promote ring closing to form lactones. Therefore, new technologies for the selective isomerization of muconic acid are urgently needed. Here, we studied the corresponding reaction kinetics to elucidate the mechanisms involved in both the isomerization and cyclization reactions with the objective to identify conditions that favor the selective formation of trans,trans-muconic acid. We demonstrate that the reactivity of muconic acid in aqueous media strongly depends on pH. Under alkaline conditions, cis,cis-muconic acid is deprotonated to the corresponding muconate dianion. This species is stable for extended periods of time and does not isomerize. Conversely, cis,cis-muconic acid readily isomerizes to its cis,trans-isomer under acidic conditions. Prolonged heating further triggers the intramolecular cyclizations through reaction of the carboxylic acid and alkene functionalities. The formation of the muconolactone and its dilactone is kinetically favored over the isomerization to trans,trans-muconic acid over a broad range of conditions. However, strategies involving the chelation of the carboxylates with inorganic salts or their solvation using polar aprotic solvents were found to hamper the ring closing reactions and allow the isomerization to trans,trans-muconic acid to proceed with high selectivity (88%). The obtained compound was further reacted with ethylene and hydrogenated to 1,4-cyclohexanedicarboxylic acid, an important monomer for the polyester and polyamide industries.This is a manuscript of an article published as Carraher, Jack M., Toni Pfennig, Radhika G. Rao, Brent H. Shanks, and Jean-Philippe Tessonnier. "cis, cis-Muconic acid isomerization and catalytic conversion to biobased cyclic-C 6-1, 4-diacid monomers." Green Chemistry 19, no. 13 (2017): 3042-3050. DOI: 10.1039/C7GC00658F . Posted with permission.</p

Solvent-driven isomerization of cis,cis-muconic acid for the production of specialty and performance-advantaged cyclic biobased monomers

The quest for green plastics calls for new routes to aromatic monomers using biomass as a feedstock. Suitable feedstock molecules and conversion pathways have already been identified for several commodity aromatics through retrosynthetic analysis. However, this approach suffers from some limitations as it targets a single molecule at a time. A more impactful approach would be to target bioprivileged molecules that are intermediates to an array of commodity and specialty chemicals along with novel compounds. Muconic acid (MA) has recently been identified as a bioprivileged intermediate as it gives access to valuable aliphatic and cyclic diacid monomers including terephthalic acid (TPA), 1,4-cyclohexanedicarboxylic acid (CHDA), and novel monounsaturated 1,4-cyclohexenedicarboxylic acids (CH1DA, CH2DA). However, accessing these cyclic monomers from MA requires to first isomerize biologically-produced cis,cis-MA to Diels–Alder active trans,trans-MA. A major impediment in this isomerization is the irreversible ring closing of MA to produce lactones. Herein, we demonstrate a green solvent-mediated isomerization using dimethyl sulfoxide and water. The mechanistic understanding achieved here elucidates the role of low concentrations of water in reducing the acidity of the system, thereby preventing the formation of lactones and improving the selectivity to trans,trans-MA from less than 5% to over 85%. Finally, a Diels–Alder reaction with trans,trans-MA is demonstrated with ethylene. The monounsaturated cyclic diacid obtained through this reaction (CH1DA) can be converted in a single step into TPA and CHDA, or can be directly copolymerized with adipic acid and hexamethylenediamine to tailor the thermal and mechanical properties of conventional Nylon 6,6.This article is published as Carraher, Jack M., Prerana Carter, Radhika G. Rao, Michael J. Forrester, Toni Pfennig, Brent H. Shanks, Eric W. Cochran, and Jean-Philippe Tessonnier. "Solvent-driven isomerization of cis, cis-muconic acid for the production of specialty and performance-advantaged cyclic biobased monomers." Green Chemistry 22, no. 19 (2020): 6444-6454. DOI: 10.1039/D0GC02108C. Copyright 2020 The Royal Society of Chemistry. Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0). Posted with permission