Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.</p

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum

Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer’s disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions

Towards an additive manufactured macroencapsulation device for islet cell replacement therapy

Islet encapsulation devices can induce a Foreign Body Response (FBR) and the formation of a hardened avascular fibrotic capsule. This FBR is heightened when the device features a smooth surface as fibrous tissue is unable to adhere to the device, causing friction and thus instigating a substantial immunological reaction causing implant failure. In this thesis we examine whether additive manufactured multiscale porous topographies can promote optimal tissue integration and vascularisation for the purpose of long-term functional islet macroencapsulation devices. Devices exhibiting progressively more complex surface topographies (quantity of pores, microtexture and macrotexture) were implanted subcutaneously in a rodent model. Upon explant, analysis of the fibrous capsule, angiogenic and macrophage response were performed. To determine whether this macroencapsulation device can support syngeneic islet survival and function, intra-peritoneal delivery of islets encapsulated within multiscale porosity macroencapsulation devices was performed in an STZ-induced diabetes rodent model. To validate scalability and functionality, devices were implanted in an STZ-induced diabetes pig model for two weeks before the blood glucose levels were measured in response to the infusion of insulin through the device. SEM and MicroCT imaging demonstrated no tissue attachment and a noticeable void between the smooth surface devices and surrounding tissue. A significant increase in capsule thickness, vessel density and maturity were associated with complex surface topographies with no difference in macrophage populations. Moreover, macroencapsulated syngeneic islets maintained glucose responsiveness and function for up to 8 weeks. Bioavailability was equal when the same dose of insulin is delivered via the device vs subcutaneously in a diabetic pig model. The additive manufactured multiscale porous topographies we developed on silicone macroencapsulation devices increased tissue integration, vascularity and supported extended islet function in vivo. Our findings demonstrated clinical scalability and large animal functionality with the ability to resolve diffusion limitations of current macroencapsulation devices. We aim to continue the translation of the multiscale porosity macroencapsulation device and improve the outcomes of people with Type 1 diabetes through the development of viable, long term implants.2021-10-2

Towards an additive manufactured macroencapsulation device for islet cell replacement therapy

Islet encapsulation devices can induce a Foreign Body Response (FBR) and the formation of a hardened avascular fibrotic capsule. This FBR is heightened when the device features a smooth surface as fibrous tissue is unable to adhere to the device, causing friction and thus instigating a substantial immunological reaction causing implant failure. In this thesis we examine whether additive manufactured multiscale porous topographies can promote optimal tissue integration and vascularisation for the purpose of long-term functional islet macroencapsulation devices. Devices exhibiting progressively more complex surface topographies (quantity of pores, microtexture and macrotexture) were implanted subcutaneously in a rodent model. Upon explant, analysis of the fibrous capsule, angiogenic and macrophage response were performed. To determine whether this macroencapsulation device can support syngeneic islet survival and function, intra-peritoneal delivery of islets encapsulated within multiscale porosity macroencapsulation devices was performed in an STZ-induced diabetes rodent model. To validate scalability and functionality, devices were implanted in an STZ-induced diabetes pig model for two weeks before the blood glucose levels were measured in response to the infusion of insulin through the device. SEM and MicroCT imaging demonstrated no tissue attachment and a noticeable void between the smooth surface devices and surrounding tissue. A significant increase in capsule thickness, vessel density and maturity were associated with complex surface topographies with no difference in macrophage populations. Moreover, macroencapsulated syngeneic islets maintained glucose responsiveness and function for up to 8 weeks. Bioavailability was equal when the same dose of insulin is delivered via the device vs subcutaneously in a diabetic pig model. The additive manufactured multiscale porous topographies we developed on silicone macroencapsulation devices increased tissue integration, vascularity and supported extended islet function in vivo. Our findings demonstrated clinical scalability and large animal functionality with the ability to resolve diffusion limitations of current macroencapsulation devices. We aim to continue the translation of the multiscale porosity macroencapsulation device and improve the outcomes of people with Type 1 diabetes through the development of viable, long term implants.2021-10-2

Notes on the preparatio and assay of anti-lymphocyte serum for use in mice

The `activity' of rabbit anti-mouse ALS was measured in terms of its power to prolong the life of A-strain homografts on CBA mice. Antisera raised by lymphocytes from mice of other strains were active in CBA mice, and conversely antisera raised by CBA lymphocytes were active in mice of other strains. All active sera were cytotoxic to mouse lymphocytes in the presence of mouse complement, but not all cytotoxic sera were active. ALS raised in species (chicken, duck) of which the sera do not bind with mouse complement were inactive in mice. Neither cytotoxicity nor the power to circumvent graft-versus-host reactions give adequate measures of the activity of impure antisera. Good antiserum (`two-pulse' ALS) for use in mice could be raised in New Zealand White rabbits by the intravenous injection of 10(9) mouse thymocytes on two occasions 14 days apart, followed by bleeding out 7 days after the second injection. Further injections of antigen increased the titre of undesirable contaminants in ALS (e.g. red cell agglutinins) but usually did not increase (and sometimes lowered) activity. ALS raised with adjuvants, though powerful, was highly toxic and required extensive absorption

Monitoring the macrophage response towards biomaterial implants using label-free imaging

Understanding the immune system's foreign body response (FBR) is essential when developing and validating a biomaterial. Macrophage activation and proliferation are critical events in FBR that can determine the material's biocompatibility and fate in vivo. In this study, two different macro-encapsulation pouches intended for pancreatic islet transplantation were implanted into streptozotocin-induced diabetes rat models for 15 days. Post-explantation, the fibrotic capsules were analyzed by standard immunohistochemistry as well as non-invasive Raman microspectroscopy to determine the degree of FBR induced by both materials. The potential of Raman microspectroscopy to discern different processes of FBR was investigated and it was shown that Raman microspectroscopy is capable of targeting ECM components of the fibrotic capsule as well as pro and anti-inflammatory macrophage activation states, in a molecular-sensitive and marker-independent manner. In combination with multivariate analysis, spectral shifts reflecting conformational differences in Col I were identified and allowed to discriminate fibrotic and native interstitial connective tissue fibers. Moreover, spectral signatures retrieved from nuclei demonstrated changes in methylation states of nucleic acids in M1 and M2 phenotypes, relevant as indicator for fibrosis progression. This study could successfully implement Raman microspectroscopy as complementary tool to study in vivo immune-compatibility providing insightful information of FBR of biomaterials and medical devices, post-implantation