Genetic Susceptibility Factors Research Articles

Domain-Specific Physical Activity and Stroke in Sweden

Associations of domain-specific physical activity with stroke incidence and poststroke outcomes have not been extensively studied using long-term, population-based data. To investigate associations of leisure time, work time, transport, and household physical activity with stroke incidence and death or dependency in activities of daily living (ADL) 3 months after stroke. The prospective, population-based Interplay Between Genetic Susceptibility and External Factors (INTERGENE) cohort study was conducted among a random sample of individuals from an urban-rural area covering western Sweden; 3614 individuals aged 24 to 77 years were examined in 2001 to 2004, and 1394 individuals were reexamined in 2014 to 2016. The median (range) follow-up was 20.0 years (56 days to 21.9 years). Data were analyzed from September through October 2023. Physical activity levels were self-reported for leisure time, work time, transportation, and household domains. The mean number of steps taken over a 6-day period was collected in a subgroup of participants using a sealed pedometer. Follow-up for stroke incidence and mortality rates continued until December 31, 2022. The composite outcome of death or ADL dependency was assessed at 3 months after stroke. Among 3614 individuals (mean [SD] age, 51.4 [13.1] years; 1910 female [52.9%]); 269 individuals (7.4%) developed stroke, of whom 120 individuals (44.6%) were dead or ADL dependent at 3 months. Intermediate (adjusted hazard ratio [aHR], 0.54; 95% CI, 0.38-0.77) and high (aHR, 0.47; 95% CI, 0.31-0.73) levels of leisure time physical activity were associated with a reduced incidence of stroke compared with low levels, as was an intermediate level of physical activity in transportation (aHR, 0.69; 95% CI, 0.52-0.93). High levels of leisure time physical activity were also associated with a reduced risk of poststroke death or ADL dependency (adjusted odds ratio, 0.34; 95% CI, 0.16-0.71) compared with low levels. Work time and household physical activity were not associated with stroke incidence or stroke outcomes. In exploratory subgroup analyses, there were interactions between physical activity and smoking (current smoking or smoking in the past year associated with stroke risk only in participants with low or intermediate physical activity: aHR, 2.33; 95% CI, 1.72-3.15) and family history of stroke (first-degree relative with a history of stroke associated with stroke risk only in participants with low or intermediate physical activity: aHR, 1.73; 95% CI, 1.27-2.38). In this study, leisure time and transport-related physical activities were associated with a reduced risk of stroke. A high level of leisure time physical activity was also associated with a lower risk of death or ADL dependency 3 months after stroke.

Alzheimer's disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice.

Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.

Assessment of genetic and clinical factors in T2D susceptibility among patients with hypertension.

Hypertension (HTN) and Type 2 Diabetes (T2D) often coexist, therefore understanding the relationship between both diseases is imperative to guide targeted prevention/therapy. This study aims to explore the relationship between HTN and T2D using genome-wide association study (GWAS) analysis and biochemical data to understand the implication of both clinical and genetic factors in these pathologies. A total of 2,876 patients were enrolled. Using GWAS and biochemical data, patients with both T2D and HTN were compared to patients with only HTN. Specificity was confirmed by testing the detected genetic variants for associations with HTN development in T2D patients, or with HTN in healthy subjects. Regression models were applied to examine the association of T2D in patients with HTN with cardiovascular risk factors. Replication was performed using UK Biobank dataset with 31,170 subjects. Data showed that females with HTN are at higher risk of developing T2D due to dyslipidemia, while males faced higher risk due to high BMI (body mass index) and family history of T2D. GWAS identified Single Nucleotide Polymorphisms (SNPs) linked to T2D in patients with HTN. Notably, rs7865889, rs7756992, and rs10896290 were positively associated with T2D, whereas rs12737517 yielded negative association. Three SNPs were replicated in the UK Biobank (rs10896290, rs7865889, and rs7756992). Incorporating clinical and genetic screening into risk assessment is important for the detection and prevention of T2D in patients with HTN. The detected SNPs (rs7865889, rs12737517, and rs10896290), especially the protective SNP (rs12737517), provide an opportunity for better diagnosis, prevention, and therapy of patients with T2D and HTN.

Central Serous Chorioretinopathy: Epidemiology, Genetics and Clinical Features.

Central serous chorioretinopathy (CSCR) is the fourth most common medical retinal disease. Moderate vision loss occurs in approximately one-third of patients who have the chronic form of the disease. CSCR has a multifactorial etiology, with acquired risk factors and increasing evidence of genetic susceptibility factors. The detection of new gene variants in CSCR and association of these variants with age-related macular degeneration provide insights into possible disease mechanisms. The contribution of multimodal ocular imaging and associated research studies to the modern-day clinical investigation of CSCR has been significant. This review aims to provide an overview of the most significant epidemiological and genetic studies of CSCR, in addition to describing its clinical and multimodal imaging features. The review also provides an update of the latest evidence from studies investigating pathophysiological mechanisms in CSCR and current opinions on multimodal imaging to better classify this complex retinal disease.

Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract

IntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression.MethodsWe performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database.ResultsAcross tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data.DiscussionOur results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.

Mucosa-Associated Lymphoid Tissue Surgeries as a Possible Risk for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory gastrointestinal disorders that are caused by genetic susceptibility and environmental factors and affects a significant portion of the global population. The gut-associated lymphoid tissue (GALT) is known to play a crucial role in immune modulation and maintaining gut microbiota balance. Dysbiosis in the latter has a known link to IBD. Therefore, the increasing prevalence of adenoidectomy in children should be explored for its potential association with IBD. The objective of this paper was to assess the association between adenoid tissue removal and the risk of developing Crohn's disease (CD) and ulcerative colitis (UC). We conducted a pooled meta-analysis to evaluate the extended clinical outcomes in patients who underwent appendicectomy and tonsillectomy compared to those who did not. Our approach involved systematically searching the PubMed database for relevant observational studies written in English. We followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines to collect data from various time periods, and to address the diversity in study results; we employed a random-effects analysis that considered heterogeneity. For outcomes, odds ratios (ORs) were pooled using a random-effects model. Seven studies, out of a total of 114,537, met our inclusion criteria. Our meta-analysis revealed a significant association between appendicectomy and CD (OR: 1.57; 95% confidence interval (CI): 1.01 - 2.43; heterogeneity I2 = 93%). Similarly, we found a significant association between tonsillectomy and CD (OR: 1.93; 95% CI: 0.96 - 3.89; I2 = 62%). However, no significant association was observed between appendicectomy and UC (OR: 0.60; 95% CI: 0.24 - 1.47; I2 = 96%), while a modest association was found between tonsillectomy and UC (OR: 1.24; 95% CI: 1.18 - 1.30; I2 = 0%). In summary, we found that the trend of appendicectomy is linked to higher odds of CD, and tonsillectomy is more likely associated with increased odds for both CD and UC, with a risk of bias present.

HLA Class II Allele Groups Involved in Autoimmune Thyroid Diseases: Hashimoto's Thyroiditis and Basedow-Graves Disease.

Autoimmune thyroid diseases (AITD), particularly Hashimoto's thyroiditis (HT) and Basedow-Graves disease (BGD) are diseases of global public health concern, characterized by autoimmune attacks on the thyroid gland, leading to hypothyroidism in HT and hyperthyroidism in BGD. We conducted a study between 2019 and 2021 in northwestern Transylvania (Romania) on patients with HT and with BGD compared to the control group. The aim of the study was to investigate the correlations of HLA class II alleles with AITD by identifying potential genetic susceptibility factors such as HLA-DRB1 and HLA-DQB1 genes in patients diagnosed with HT and BGD. Various molecular biology methods, including SSP-PCR low-resolution and PCR-SSO were employed to analyze DNA samples from patients and control subjects. Our study revealed the influence of the HLA-DRB1*03/*16 genotype as a genetic susceptibility factor for HT, a similar influence regarding BGD being observed for the HLA-DRB1*03 allele group, DRB1*03/*16 genotype, and the DRB1*03/DQB1*06 haplotype. The only protective factor detected in our study was the HLA-DRB1*13 allele group, for both HT and BGD. By elucidating any specific allele or genotype associations that might contribute to the development of AITD, our study can contribute to the prevention and early detection of these diseases.

Identification of a de novo CACNA1B variant and a start-loss ADRA2B variant in paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) represents the most prevalent form of paroxysmal dyskinesia, characterized by recurrent and transient attacks of involuntary movements triggered by a sudden voluntary action. In this study, whole-exome sequencing was conducted on a cohort of Chinese patients to identify causal mutations. In one young female case, a de novo CACNA1B variant (NM_000718.3:exon3:c.479C > T:p.S160F) was identified as the causative lesion. This finding may broaden the phenotypic spectrum of CACNA1B mutations and provide a prospective cause of primary PKD. Additionally, a novel start-loss variant (NM_000682.7:c.3G > A) within ADRA2B further denied its association with benign adult familial myoclonic epilepsy, and a KCNQ2 E515D variant that was reported as a genetic susceptibility factor for seizures had no damaging effect in this family. In sum, this study established a correlation between CACNA1B and primary PKD, and found valid evidence that further negates the pathogenic role of ADRA2B in benign adult familial myoclonic epilepsy.

Associations of polychlorinated biphenyls exposure, lifestyle, and genetic susceptibility with dyslipidemias: Evidence from a general Chinese population

Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals that have been associated with various adverse health conditions. Herein we explored the associations of PCBs with dyslipidemia and further assessed the modification effect of genetic susceptibility and lifestyle factors. Six serum PCBs (PCB-28, 101, 118, 138, 153, 180) were determined in 3845 participants from the Wuhan-Zhuhai cohort. Dyslipidemia, including hyper-total cholesterol (HyperTC), hyper-triglyceride (HyperTG), hyper-low density lipoprotein cholesterol (HyperLDL-C), and hypo-high density lipoprotein cholesterol (HypoHDL-C) were determined, and lipid-specific polygenic risk scores (PRS) and healthy lifestyle score were constructed. We found that all six PCB congeners were positively associated with the prevalence of dyslipidemias, and ΣPCB level was associated with HyperTC, HyperTG, and HyperLDL-C in dose-response manners. Compared with the lowest tertiles of ΣPCB, the odds ratios (95% confidence intervals) in the highest tertiles were 1.490 (1.258, 1.765) for HyperTC, 1.957 (1.623, 2.365) for HyperTG, and 1.569 (1.316, 1.873) for HyperLDL-C, respectively. Compared with those with low ΣPCB, healthy lifestyle, and low genetic risk, participants with high ΣPCB, unfavorable lifestyle, and high genetic risk had the highest odds of HyperTC, HyperTG, and HyperLDL-C. Our study provided evidence that high PCB exposure exacerbated the association of genetic risk and unhealthy lifestyle with dyslipidemia.

Advances in the pathogenesis of vulvar lichen sclerosus.

Vulvar lichen sclerosus (VLS) is a chronic non-neoplastic skin lesion characterized by vulvar itching, pain, atrophy, whitening of the skin and mucous membranes, and gradual atrophy and disappearance of the labia minora, which can eventually lead to vulvar scarring, causing functional impairment and seriously affecting the patient's physical and mental health. VLS can occur at any age, however, its pathogenesis and etiology are not fully understood. Considerable progress has been made in related research on genetic susceptibility factors, autoimmune disorders, collagen metabolism abnormalities, and their triggering factors in disease formation and progression. This article reviews the etiology of vulvar lichen sclerosus.

Invertebrate genetic models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by the progressive death of motor neurons in the cerebral cortex, brain stem, and spinal cord. The exact mechanisms underlying the pathogenesis of ALS remain unclear. The current consensus regarding the pathogenesis of ALS suggests that the interaction between genetic susceptibility and harmful environmental factors is a promising cause of ALS onset. The investigation of putative harmful environmental factors has been the subject of several ongoing studies, but the use of transgenic animal models to study ALS has provided valuable information on the onset of ALS. Here, we review the current common invertebrate genetic models used to study the pathology, pathophysiology, and pathogenesis of ALS. The considerations of the usage, advantages, disadvantages, costs, and availability of each invertebrate model will also be discussed.

Inclusion Body Myositis in Children: Does it Exist?

Context: Sporadic inclusion body myositis (sIBM) is a rare type of juvenile idiopathic inflammatory myopathies (JIIMs). It mainly affects skeletal muscles but can also affect the skin and other organs in the body. Sporadic inclusion body myositis prevalence in children under 18 years old is very rare. Objectives: This review provides an overview of the evidence of sIBM in children, discusses the possible clinical and pathological features, and explores the proposed pathogenesis. Methods: A literature review of over 44 articles in PubMed and other medical libraries, such as Google Scholar and Web of Science, was carried out using terms such as JIIM, IBM, Inflammatory Myopathies in Children, and Inherited IBM. Two documented reports for sIBM were found, and the rest included the disease pathogenesis, prevalence of inherited IBM, and other myopathies in children. Results: This review discussed the prevalence and incidence of JIIM, in particular sIBM in children. While IBM is typically sporadic, there have been rare cases where it is familial and inherited. Genetic susceptibility factors are believed to play a role in sIBM. Most patients with sIBM are over 50 years old and experience significant weakness in the quadriceps; however, patients with inherited IBM (h-IBM) typically present earlier in adulthood with a distinct pattern of weakness. Sporadic inclusion body myositis can be misdiagnosed as other forms of myopathies, such as juvenile dermatomyositis (JDM) or limb-girdle muscular dystrophy (LGMD), during the early stages of the disease. The exact causes of sIBM are still unknown; however, environmental factors, genetic predispositions, and immune dysregulation might contribute to the pathogenesis of the disease. Conclusions: Sporadic inclusion body myositis is a rare form of JIIMs. Its early diagnosis in children can be challenging due to the presence of other coexisting diseases. Discussions have revolved around potential environmental factors, such as viral infections, specific myositis-specific antibodies (MSAs), such as anti-Ro52, and possibly certain human leukocyte antigen (HLA) haplotypes. Given the rarity of reported cases of sIBM in children, it is important to encourage further studies to better understand the underdiagnosed instances of this condition.

The key role of miRNA in syndromic and sporadic forms of ascending aortic aneurysms as biomarkers and targets of novel therapeutic strategies.

Increasing evidence shows that epigenetics also plays a key role in regulating the pathogenetic mechanism of all types of aortic aneurysms. It is well-known that epigenetic factors modulate gene expression. This mechanism appears to be of interest especially knowing the relevance of genetic susceptibility and genetic factors in the complex pathophysiology of aortic aneurysms, and of sporadic forms; in fact, the latter are the result of a close interaction between genetic and modifiable lifestyle factors (i.e., nutrition, smoking, infections, use of drugs, alcohol, sedentary lifestyle, etc.). Epigenetic factors include DNA methylation, post-translational histone modifications, and non-coding RNA. Here, our attention is focused on the role of miRNA in syndromic and sporadic forms of thoracic aortic aneurysms. They could be both biomarkers and targets of novel therapeutic strategies.

Genetic and environmental influence on alcohol intent and alcohol sips among U.S. children-Effects across sex, race, and ethnicity.

Alcohol intent (the susceptibility to initiating alcohol use) and alcohol sips (the initiation of alcohol) in youth are a multifactorial puzzle with many components. This research aims to examine the connection between genetic and environmental factors across sex, race and ethnicity. Data was obtained from the twin hub of the Adolescent Brain Cognitive Development (ABCD) study at baseline (2016-2018). Variance component models were conducted to dissect the additive genetic (A), common (C) and unique environmental (E) effects on alcohol traits. The proportion of the total alcohol phenotypic variation attributable to additive genetic factors is reported as heritability (h2). The sample (n = 1,772) included an approximately equal male-female distribution. The 886 same-sex twin pairs were 60.4% dizygotic (DZ), 39.6% monozygotic (MZ), 65.4% non-Hispanic Whites, 13.9% non-Hispanic Blacks, 10.8% of Hispanics with a mean age of 121.2 months. Overall, genetic predisposition was moderate for alcohol intent (h2 = 28%, p = .006) and low for alcohol initiation (h2 = 4%, p = 0.83). Hispanics (h2 = 53%, p < .0001) and Blacks (h2 = 48%, p < .0001) demonstrated higher alcohol intent due to additive genetic factors than Whites (h2 = 34%, p < .0001). Common environmental factors explained more variation in alcohol sips in females (c2 = 63%, p = .001) than in males (c2 = 55%, p = .003). Unique environmental factors largely attributed to alcohol intent, while common environmental factors explained the substantial variation in alcohol initiation. Sex and racial/ethnic disparities in genetic and environmental risk factors for susceptibility to alcohol initiation can lead to significant health disparities. Certain populations may be at greater risk for alcohol use due to their genetic and ecological factors at an early age.

Effect of Toll-Like Receptor 9 (TLR9) in Breast Cancer Risk, Along with Hormonal Effects in Patients Receiving Radiotherapy

Introduction: Antioxidant enzyme polymorphisms and innate immune receptors have been implicated in the development of various cancer forms. This study aimed to assess the potential association between toll-like receptor 9 (TLR9) polymorphisms and female susceptibility to breast cancer. Methods: Forty female breast cancer patients from Iraq and 20 healthy volunteers were enrolled in the study. Gene polymorphisms of TLR9 rs187084 (1237T/C) were analyzed using real-time polymerase chain reaction (RT-PCR). Additionally, a hormonal study was conducted, comparing breast cancer patients exposed to radiation with a control group. The levels of follicle-stimulating hormone (FSH), estradiol (E2), and progesterone were measured. Results: The analysis revealed a non-significant increase in the prevalence of TLR9 wild TT genotypes among breast cancer patients compared to healthy individuals (72.5% vs. 90%, respectively). Conversely, heterozygous CT genotypes were significantly higher in breast cancer patients compared to healthy women (22.5% vs. 10%, P&lt;0.05). In the hormonal study, breast cancer patients exposed to radiation exhibited a significant increase in FSH levels (2.9 vs. 18.8 IU/ml), a significant decrease in E2 levels (0.232 vs. 0.910 pico/ml), and a significant increase in progesterone levels (0.910 vs. 0.732 nanogram/ml). Conclusion: The study concludes that TLR9 rs187084 (1237T/C) polymorphism variants play crucial roles in the susceptibility of Iraqi females to breast cancer. Furthermore, the observed hormonal disruptions in FSH, E2, and progesterone levels highlight potential contributors to breast cancer development, emphasizing the need for further exploration of genetic and hormonal factors in cancer susceptibility.

Gene-Environment Interactions for Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures in the 23andMe, Inc. research dataset. Using a validated PD polygenic risk score and common PD-associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and 7 lifestyle and environmental factors: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA). We observed that T2D, as well as higher BMI, caffeine consumption, and tobacco use, were associated with lower odds of PD, whereas head injury, pesticide exposure, GBA carrier status, and PD polygenic risk score were associated with higher odds. No significant association was observed between PA and PD. In interaction analyses, we found statistical evidence for an interaction between polygenic risk of PD and the following environmental/lifestyle factors: T2D (p = 6.502 × 10-8), PA (p = 8.745 × 10-5), BMI (p = 4.314 × 10-4), and tobacco use (p = 2.236 × 10-3). Although BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D, as well as PD and PA, varied depending on polygenic risk score. We provide preliminary evidence that associations between some environmental and lifestyle factors and PD may be modified by genotype. ANN NEUROL 2024;95:677-687.

DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line. Mice with heterozygous RELN haploinsufficiency were crossed with mice expressing dominant-negative c-terminal truncated human DISC1 to produce offspring with both mutations (HRM/DISC1 mice). We used an array of behavioral tests to generate a behavioral phenotype for these mice, then examined the prefrontal cortex and hippocampus using western blotting and immunohistochemistry to probe for SCZ-relevant molecular and cellular alterations. Compared to wild-type controls, HRM/DISC1 mice demonstrated impaired pre-pulse inhibition, altered cognition, and decreased activity. Diazepam failed to rescue anxiety-like behaviors, paradoxically increasing activity in HRM/DISC1 mice. At a cellular level, we found increased α1-subunit containing GABA receptors in the prefrontal cortex, and a reduction in fast-spiking parvalbumin positive neurons. Maturation of adult-born neurons in the hippocampus was also altered in HRM/DISC1 mice. While there was no difference in the total number proliferating cells, more of these cells were in immature stages of development. Homozygous DISC1 mutation combined with RELN haploinsufficiency produces a complex phenotype with neuropsychiatric characteristics relevant to SCZ and related disorders, expanding our understanding of how multiple genetic susceptibility factors might interact to influence the variable presentation of these disorders.

Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN – a multi-view, weakly-supervised deep clustering method – which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer’s disease and brain endophenotypes associated with hypertension, from MRI and single nucleotide polymorphism data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-associated neuroimaging phenotypes.

Recent advances in the genetics of familial and sporadic ALS.

ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.

The causal relationship between risk of developing bronchial asthma and frailty: a bidirectional two-sample Mendelian randomization study.

A potential link between asthma and frailty has been suggested in previous studies. However, the nature of the causal relationship between these two conditions warrants further investigation. Therefore, this study assessed the bidirectional causality between asthma and frailty risk using two-sample Mendelian randomization (MR). The study data were obtained from the genome-wide association study (GWAS) dataset, with 337,159 samples representing asthma data and 175,226 samples representing frailty. The causal relationship between the two disorders was assessed by selecting the single nucleotide polymorphisms (SNPs), significantly associated with both asthma and frailty. The inverse variance weighting (IVW) method was used as the main analytical method to estimate the possible influence of causality. Sensitivity analysis was also performed using Mr-Egger intercept, funnel plot, "leave-one-out," and Cochran Q test. In addition, potential mediators were investigated by risk factor analysis. The IVW method showed an increased risk of frailty due to increased genetic susceptibility factors and the number of to asthma (OR = 2.325, 95%CI:1.958-2.761; p = 6.527498e-22), while no horizontal pleiotropy was observed for the Mr-Egger intercept (p = 0.609) and the funnel plot. The Cochran Q value was 72.858, p = 0.024, and there was heterogeneity in the Cochran Q-value. No single SNP was observed for "leave-one-out" that had a biasing effect on the instrumental variables. In addition, genetic susceptibility to frailty was associated with asthma (OR = 1.088, 95%CI:1.058-1.119; p = 4.815589e-09). In the causal relationship described above, several risk factors for frailty are complex, with asthma leading to a significant reduction in physical activity endurance. Our findings suggest a probable positive causal effect of asthma on the risk of developing frailty, potentially mediated by reduced physical activity endurance. At the same time, a causal relationship exists between frailty and asthma. Therefore, assessment strategies for frailty should include asthma and vice versa.