Neurological Traits Research Articles

Network Analysis of Brain and Bone Tissue Transcripts Reveals Shared Molecular Mechanisms Underlying Alzheimer's Disease and Related Dementias and Osteoporosis.

Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are 2 prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown. We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these 2 diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in 5 ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of coexpressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered 3 modules in ROSMAP that showed significant associations with ADRD and bone-related traits and 4 modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the 2 networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest. These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP.

Effect of genetic clusters related to insulin resistance on neurological traits in diverse populations from the Trans‐Omics for Precision Medicine Program

AbstractBackgroundInsulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) and is primarily driven by obesity, another AD risk factor. The biological mechanism by which IR predisposes to AD is unknown. Genetic clustering analyses of type 2 diabetes (T2D) loci can help characterize which mechanism of impaired insulin action may be involved in AD and related traits.MethodWe constructed five genetic clusters related to IR (Obesity, Lipodystrophy, Liver/Lipid, ALP [alkaline phosphatase] negative, and Hyper‐Insulin Secretion) based on a recent clustering analysis of T2D loci (PMID: 36538063). We evaluated the association of each cluster with the Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR) and neurological traits (AD, dementia, general cognitive function, and four brain MRI volumes) in >38k participants (36% men, mean age 55yrs (14.5)) of diverse race or ethnicity, from the Trans‐Omics for Precision Medicine (TOPMed) Program. We conducted pooled and race/ethnicity‐stratified association analyses (European‐50%, African‐American‐22.5%, and Hispanic/Latino‐21%). We used logistic or linear mixed‐effect models, adjusted for age, sex, study, and the first 11 genetic principal components. We accounted for relatedness and allowed for heterogeneous variances across studies.ResultWe confirmed the association of each IR genetic cluster with HOMA‐IR in the pooled analysis (2.6E‐66≤P≤2E‐4) and detected significant to suggestive associations in group‐stratified analyses (6.3E‐39≤P≤0.05), except for the Hyper‐Insulin Secretion cluster in African‐Americans (P = 0.30). The genetic clusters were not significantly associated with neurological outcomes after multiple testing adjustment (P = 0.05/Ngroups/Nclusters/Noutcomes = 0.05/4/5/7 = 3.6×10−4). We observed nominal associations (P<0.05) for two genetic clusters. The Lipodystrophy cluster was negatively associated with intracranial volume in the pooled analysis (beta = ‐0.51, P = 0.003) as well as in European (beta = ‐0.47, P = 0.02) and Hispanic/Latino (beta = ‐1.23, P = 0.01) participants. The Hyper‐Insulin Secretion cluster was negatively associated with hippocampal volume in Hispanic/Latino participants (beta = ‐0.005, P = 0.03), and positively associated with AD and dementia (OR = 1.02 [1.001‐1.038], P = 0.03) in European participants.ConclusionOur findings are consistent with the literature suggesting that IR may be associated with lower brain volumes and increased AD risk. Our analyses shed light on two biological mechanisms of impaired insulin action potentially involved in AD and related traits, with genetic associations that may differ by race or ethnicity.Funding: R00AG066849

Genome‐wide Association Study Meta‐analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

AbstractBackgroundNeurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro‐axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders.MethodTo identify the genetic variations underlying blood NfL levels, we conducted an ancestry‐specific meta‐analyses of genome‐wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African‐American ancestry. In the post‐GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD‐regression, and genetic risk score (GRS) association analysis with neurological traits.ResultIn the European ancestry GWAS meta‐analysis, we identified two genome‐wide significant (P< 5×10−8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African‐American ancestry GWAS meta‐analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta‐analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer’s disease (AD) (rg = 0.32, P = 1.74×10−6), total‐tau (rg = 2.01, P = 1.03×10−6), amyloid‐beta (Aβ)‐40 (rg = 0.80, P = 6.92×10−6),and Aβ‐42 (rg = 1.03, P = 4.39×10−5). A higher genetic risk score based on NfL‐associated genetic variants was also related to increased plasma levels of total‐tau (P = 1.97×10−4), Aβ‐ 40 (P = 2.24×10−5), Aβ‐42 (P = 2.92×10−4) in the Rotterdam Study.ConclusionThis large‐scale GWAS meta‐analysis revealed multiple novel genetic loci of NfL levels in blood in participants from European and African‐American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ‐42, and total‐tau may indicate a common underlying pathway of neurodegeneration.

Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus

BackgroundInsulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.MethodsWe conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified DNA methylation markers associated with IR at the genome-wide level accounting for multiple testing (P < 1.1 × 10−7) and evaluated their association with neurological traits in participants from the FHS (N = 3040) and the Religious Orders Study/Memory and Aging Project (ROSMAP, N = 707). DNA methylation profiles were measured in blood (FHS) or dorsolateral prefrontal cortex (ROSMAP) using the Illumina HumanMethylation450 BeadChip. Linear regressions (ROSMAP) or mixed-effects models accounting for familial relatedness (FHS) adjusted for age, sex, cohort, self-reported race, batch, and cell type proportions were used to assess associations between DNA methylation and neurological traits accounting for multiple testing.ResultsWe confirmed the strong association of blood DNA methylation with IR at three loci (cg17901584–DHCR24, cg17058475–CPT1A, cg00574958–CPT1A, and cg06500161–ABCG1). In FHS, higher levels of blood DNA methylation at cg00574958 and cg17058475 were both associated with lower IR (P = 2.4 × 10−11 and P = 9.0 × 10–8), larger total brain volumes (P = 0.03 and P = 9.7 × 10−4), and smaller log lateral ventricular volumes (P = 0.07 and P = 0.03). In ROSMAP, higher levels of brain DNA methylation at the same two CPT1A markers were associated with greater risk of cognitive impairment (P = 0.005 and P = 0.02) and higher AD-related indices (CERAD score: P = 5 × 10−4 and 0.001; Braak stage: P = 0.004 and P = 0.01).ConclusionsOur results suggest potentially distinct epigenetic regulatory mechanisms between peripheral blood and dorsolateral prefrontal cortex tissues underlying IR and AD at CPT1A locus.

De novo network analysis reveals autism causal genes and developmental links to co-occurring traits.

Autism is a complex neurodevelopmental condition that manifests in various ways. Autism is often accompanied by other conditions, such as attention-deficit/hyperactivity disorder and schizophrenia, which can complicate diagnosis and management. Although research has investigated the role of specific genes in autism, their relationship with co-occurring traits is not fully understood. To address this, we conducted a two-sample Mendelian randomisation analysis and identified four genes located at the 17q21.31 locus that are putatively causal for autism in fetal cortical tissue (LINC02210, LRRC37A4P, RP11-259G18.1, and RP11-798G7.6). LINC02210 was also identified as putatively causal for autism in adult cortical tissue. By integrating data from expression quantitative trait loci, genes and protein interactions, we identified that the 17q21.31 locus contributes to the intersection between autism and other neurological traits in fetal cortical tissue. We also identified a distinct cluster of co-occurring traits, including cognition and worry, linked to the genetic loci at 3p21.1. Our findings provide insights into the relationship between autism and co-occurring traits, which could be used to develop predictive models for more accurate diagnosis and better clinical management.

Neurological injury in primary Sjogren's syndrome.

Forty-eight patients with primary Sjogren's syndrome, attending outpatient clinics at Damascus Hospital between January 2020 and January 2022 in this cross-sectional study at the outpatient clinics, were interviewed and examined, and the necessary laboratory and radiological examinations were demanded. Information was collected on disease duration, onset time, and patterns of neurological symptoms. Forty-eight patients, including 42 females, aged 56.1±10.3 years were enroled.Central nervous system involvement was found in 34 patients. 85% of patients had generalized nerve manifestations, while local nerve manifestations were found in 77,5% of patients. The common neurological manifestation was headaches, then cognitive disorders, and the most common pattern of headache was migraine. Beck Depression Index showed a significant increase in the apathy evaluation scale.The study of cognitive changes showed a significant increase in the Mini-Mental State Examination (MMSE) index.Carotid Doppler showed the presence of injury in 42.4% of patients. The magnetic resonance imaging showed positive findings in 21 patients and positive evoked potentials in 52% of patients. Studies showing the prevalence of Sjogren's neurological injury patterns are insufficient, but this was changed when the criteria for diagnosing Sjogren's syndrome was modified, and the definition of neurological traits in the context of the syndrome was expanded.The presence of a high rate of headaches, cognitive changes, and fatigue confirms that generalized nervous system injuries are more common than local injuries. Migraine was the most common pattern of headache found in patients with the syndrome compared with other patterns such as tension headaches and headaches due to medications, especially analgesics.This was associated with the presence of anti-SSA antibodies and Raynaud's phenomenon, which suggest that the headache mechanism may be due to vascular endothelial dysfunction or an immune-mediated inflammation injury of the neurovascular system.The changes that appeared on the MRI images suggested premotor cortex involvement rather than mesolimbic cortical impairment, and its presence was also associated with SSA antibody positivity, and it is caused by inflammation. Primary Sjogren's syndrome should be considered as having any unspecified or specific neurological disorder.

Extra-criteria antiphospholipid antibodies in patients with small vessel brain lesions and clinical manifestations associated with antiphospholipid syndrome

ObjectivesNeurological manifestations compatible with small vessel brain lesions (SVBL), such as migraine, cognitive impairment, seizures, and transverse myelitis, may be related to antiphospholipid syndrome (APS) and patients could need APS therapies even though they do not fit into thrombosis or obstetric morbidity. Furthermore, extra-criteria antiphospholipid antibodies (aPL) provide an increase in sensitivity in patients with clinical manifestations related to APS but negative for IgG/IgM anticardiolipin (aCL), anti-β2 glycoprotein I (aβ2GPI), and lupus anticoagulant, which are the antibodies included in the classification criteria for APS. MethodsWe determined extra-criteria aPL in 65 SVBL patients with neurological traits and Magnetic Resonance Imaging suggestive of APS but negative for APS classification criteria, 47 of whom were prospectively followed and tested over three years. A group of 95 patients with autoimmune diseases (AD) but without clinical traits of APS was also studied. ResultsA persistent presence of extra-criteria aPL was detected in 27.7% of patients: 12.77% IgM anti- prothrombin (PT), 6.38% IgG anti-PT, 6.38% IgM anti-phosphatidylethanolamine (PE), 4.26% IgA aβ2GPI, 2.13% IgG anti-phosphatidylserine/prothrombin (PS/PT) and 2.13% IgM anti-PS/PT.There was a tendency towards a higher prevalence of these aPL in SVBL patients than in AD – especially for IgA aβ2GPI – and a lack of IgG aPS/PT positivity in the AD group. We found no SVBL patient positive for IgA aCL, IgG anti-PE, annexin V, or aβ2GPI domain I. ConclusionsExtra-criteria aPL can improve sensitivity for APS diagnosis in patients with SVBL, especially IgA aβ2GPI and IgG anti-PS/PT antibodies.

Thirty novel sequence variants impacting human intracranial volume.

Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder.

Pesticide exposure, genetic susceptibility, and prostate cancer risk in the Agricultural Health Study

Background and aim: Specific pesticides have been associated with risk of prostate cancer, but interactions with genetic susceptibility loci have rarely been studied. We examined the joint associations of pesticides and genetic variants with prostate cancer risk. Methods: We studied 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of pesticide use was self-reported at enrollment. Genotyping was conducted using the OncoArray-500K BeadChip (Illumina Inc). Logistic regression models estimated the joint associations of pesticides previously linked to prostate cancer (fonofos, terbufos, malathion, aldrin, linuron, and dimethoate) and 256 individual genetic variants and an aggregated polygenic risk score (PRS) with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. Results: We observed multiplicative interaction between fonofos and the PRS in relation to risk of total and aggressive prostate cancer. Compared to the reference group (non-exposed, PRS scores &amp;#x3c;median), those with fonofos exposure and PRS scores &amp;#x3e;median had elevated risks of total (OR 1.35, 95% CI 1.06-1.73, p-int=0.03) and aggressive (OR 1.49, 95% CI 1.09-2.04, p-int=0.19) prostate cancer. There was also evidence of interaction between the six pesticides and individual genetic variants occurring in genomic regions associated with 1) cancer signaling pathways, 2) hormonal perturbations relevant for prostate cancer, 3) DNA damage response and 4) neurological traits; many of the examined pesticides have known neurologic mechanisms. Conclusion: Joint exposure to the organophosphate insecticide fonofos and genetic susceptibility may further elevate the risk for total and aggressive prostate cancer, above the independent effects of each. These results, as well as those observed for individual genetic markers, suggest potential mechanisms by which these pesticides may increase prostate cancer risk. Keyword: Prostate Cancer, Pesticides, Occupational exposure, Genetic susceptibility

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.

Parent-of-origin effects propagate through networks to shape metabolic traits.

Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F0, F1, F2, F16) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of three imprinted and six non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on two genes, Nnat and F2r, whose interaction associates with serum glucose levels across generations in high-fat-fed females. Single-cell RNAseq reveals that Nnat expression increases and F2r expression decreases in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.

PSXII-3 Identification of key metabolic mediators during dietary tryptophan supplementation in low-birth-weight pigs by RNA sequencing

Abstract Low birth weight (LBW) is associated with the development of metabolic syndrome, diabetes mellitus and insulin resistance. While tryptophan (Trp), one of essential amino acids supplied by diet, plays an essential role in fetal growth and development, the effects of Trp supplementation on metabolic processes of postnatal LBW individuals remain unclear. The objective of this study was to identify differentially expressed (DE) genes and altered biological processes in liver of LBW and normal birth weight (NBW) piglets supplemented with Trp. RNA was isolated from liver tissues of three weeks old piglets supplemented with Trp (NBW-0% and LBW-0, 0.4, and 0.8%) and was used for RNA sequencing (RNAseq). There were 100, 191 and 39 DE genes in NBW (N0) and LBW tryptophan 0.4%, 0.8% (L4 and L8) when compared to LBW without Trp supplementation (L0). To determine whether Trp supplementation can resume metabolic regulation-related gene expression to N0 level, DE genes from N0 vs. L0 were clustered into 3 groups based on co-expression trends and clusters were enriched for genes associated with lipid catabolic process, circadian regulation of gene expression and fatty acid response. Further, eight hub genes (PID1, PAFAH2, MAP3K15, ANKRD44, CYP2J34, N4BP2L1, RUSC1 and SALL1) identified in co-expression networks based on Pearson correlation coefficient had strong co-expression coefficients (|r| &amp;gt; 0.9) with each other. In particular, PID1 was significantly associated with many neurological, metabolic, environmental and cardiovascular traits based on phenome-wide association analysis (Phe-WAS). In summary, our study provides novel insights into the molecular mechanism underlying LBW metabolic changes with Trp supplementation in porcine liver tissue and highlights that LBW metabolism restoration may be regulated by genes participating in fatty acid response and cardiovascular diseases.

Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation.

Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype-Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.

CellWalker integrates single-cell and bulk data to resolve regulatory elements across cell types in complex tissues

Single-cell and bulk genomics assays have complementary strengths and weaknesses, and alone neither strategy can fully capture regulatory elements across the diversity of cells in complex tissues. We present CellWalker, a method that integrates single-cell open chromatin (scATAC-seq) data with gene expression (RNA-seq) and other data types using a network model that simultaneously improves cell labeling in noisy scATAC-seq and annotates cell type-specific regulatory elements in bulk data. We demonstrate CellWalker’s robustness to sparse annotations and noise using simulations and combined RNA-seq and ATAC-seq in individual cells. We then apply CellWalker to the developing brain. We identify cells transitioning between transcriptional states, resolve regulatory elements to cell types, and observe that autism and other neurological traits can be mapped to specific cell types through their regulatory elements.

Identification of multi‐issue protein quantitative trait loci (pQTLs) for Alzheimer disease

AbstractBackgroundAlzheimer disease (AD) is a neurodegenerative disease, affecting around 5.8 million people in the United States as of 2019. It has been widely studied, but there is still no effective treatment. Using large‐scale Genome‐wide association studies and whole genome/exome sequencing, researchers have identified common and rare variants associated disease risk that can be used to build prediction models. However, there are limited studies that use high‐throughput genomic approaches to identify novel biomarkers beyond genetic variations.MethodWe profiled 1,305 proteins using SOMAscan platform for 971 CSF, 636 plasma, and 458 parietal lobe from participants of the Knight‐ADRC. We aim to identify the genetic architecture that govern protein levels and how do these proteins modulate AD risk, age at onset, rate of progression, and additional neurodegenerative traits. To do so, we first identified protein quantitative trait loci (pQTLs) from CSF, plasma, and brain tissues. Next, we inferred causality between proteins with significant pQTLs and AD and neurodegenerative traits employing Mendelian Randomization (MR) approaches.ResultWe identified pQTLs in each tissue. We found 26, 17, and 206 novel pQTLs, in brain, plasma and CSF respectively. We also successfully replicated several reported pQTLs from CSF (e.g. rs2673908 associated with the protein Siglec‐9) and plasma (e.g. rs12740374 associated with the protein Granulins). To infer the causality between proteins and AD or other neurological diseases, we performed MR analysis by using pQTLs as instrumental variables. Overall, we processed MR framework using proteins with significant pQTLs within each tissue on seven neurological‐related traits. Known protein‐disease relationships were replicated. For example, plasma Siglec‐3 (CD33) increases the AD risk, consistent with a larger plasma‐proteome MR analyses by Zheng and colleagues in 2019. We also uncovered the novel proteins in pathways associated with AD risk and additional endophenotypes. In total, we found between 6 to 25 potential new biomarkers for AD progression, depending on the tissue we evaluated. Similarly, we identified 2 to 21 proteins associated with for AD age at onset.ConclusionTaken together, these findings prioritized the proteins for the functional validation study. Thus, the findings helped identify potential biomarkers for AD or other neurological traits.

Genome-Wide Scan for Five Brain Oscillatory Phenotypes Identifies a New QTL Associated with Theta EEG Band.

Brain waves, measured by electroencephalography (EEG), are a powerful tool in the investigation of neurophysiological traits and a noninvasive and cost-effective alternative in the diagnostic of some neurological diseases. In order to identify novel Quantitative Trait Loci (QTLs) for brain wave relative power (RP), we collected resting state EEG data in five frequency bands (δ, θ, α, β1, and β2) and genome-wide data in a cohort of 105 patients with late onset Alzheimer’s disease (LOAD), 41 individuals with mild cognitive impairment and 45 controls from Iberia, correcting for disease status. One novel association was found with an interesting candidate for a role in brain wave biology, CLEC16A (C-type lectin domain family 16), with a variant at this locus passing the adjusted genome-wide significance threshold after Bonferroni correction. This finding reinforces the importance of immune regulation in brain function. Additionally, at a significance cutoff value of 5 × 10−6, 18 independent association signals were detected. These signals comprise brain expression Quantitative Loci (eQTLs) in caudate basal ganglia, spinal cord, anterior cingulate cortex and hypothalamus, as well as chromatin interactions in adult and fetal cortex, neural progenitor cells and hippocampus. Moreover, in the set of genes showing signals of association with brain wave RP in our dataset, there is an overrepresentation of loci previously associated with neurological traits and pathologies, evidencing the pleiotropy of the genetic variation modulating brain function.

The association of clinical phenotypes to known AD/FTD genetic risk loci and their inter-relationship.

To elucidate how variants in genetic risk loci previously implicated in Alzheimer’s Disease (AD) and/or frontotemporal dementia (FTD) contribute to expression of disease phenotypes, a phenome-wide association study was performed in two waves. In the first wave, we explored clinical traits associated with thirteen genetic variants previously reported to be linked to disease risk using both the 23andMe and UKB cohorts. We tested 30 additional AD variants in UKB cohort only in the second wave. APOE variants defining ε2/ε3/ε4 alleles and rs646776 were identified to be significantly associated with metabolic/cardiovascular and longevity traits. APOE variants were also significantly associated with neurological traits. ABI3 variant rs28394864 was significantly associated with cardiovascular (e.g. (hypertension, ischemic heart disease, coronary atherosclerosis, angina) and immune-related trait asthma. Both APOE variants and CLU variant were significantly associated with nearsightedness. HLA- DRB1 variant was associated with diseases with immune-related traits. Additionally, variants from 10+ AD genes (BZRAP1-AS1, ADAMTS4, ADAM10, APH1B, SCIMP, ABI3, SPPL2A, ZNF232, GRN, CD2AP, and CD33) were associated with hematological measurements such as white blood cell (leukocyte) count, monocyte count, neutrophill count, platelet count, and/or mean platelet (thrombocyte) volume (an autoimmune disease biomarker). Many of these genes are expressed specifically in microglia. The associations of ABI3 variant with cardiovascular and immune-related traits are one of the novel findings from this study. Taken together, it is evidenced that at least some AD and FTD variants are associated with multiple clinical phenotypes and not just dementia. These findings were discussed in the context of causal relationship versus pleiotropy via Mendelian randomization analysis.

Environmental Epigenetics of Diesel Particulate Matter Toxicogenomics.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disruptions in social communication and behavioral flexibility. Both genetic and environmental factors contribute to ASD risk. Epidemiologic studies indicate that roadway vehicle exhaust and in utero exposure to diesel particulate matter (DPM) are associated with ASD. Using the Comparative Toxicogenomics Database (CTD), we identified genes connected to DPM exposure and ASD, extracted the known enhancers/promoters of the identified genes, and integrated this with Assay for Transposase Accessible Chromatin (ATAC-seq) data from DPM-exposed human neural progenitor cells. Enhancer/promoter elements with significantly different chromosome accessibility revealed enriched DNA sequence motifs with transcription factor binding sites for EGR1. Variant extraction for linkage disequilibrium blocks of these regions followed by analysis through Genome Wide Association Studies (GWAS) revealed multiple neurological trait associations including exploratory eye movement and brain volume measurement. This approach highlights the effects of pollution on the regulatory regions of genes implicated in ASD by genetic studies, indicating convergence of genetic and environmental factors on molecular networks that contribute to ASD. Integration of publicly available data from the CTD, cell culture exposure studies, and phenotypic genetics synergize extensive evidence of chemical exposures on gene regulation for altered brain development.

Effects of allele-specific open chromatin

Neurogenomics Genetic variants in noncoding regions of the genome may underlie the development of disease. However, we are just beginning to tease apart the function of such variants associated with neuropsychiatric disease. Using five types of neural progenitor cells derived from 20 human induced pluripotent stem cell lines, Zhang et al. looked at allele-specific open chromatin (ASoC) variants. Many ASoC variants overlapped with genomic elements, such as transcription factor binding sites, and loci identified in genome-wide association studies for neurological traits. From the experimental and computational analyses, they identified single-nucleotide polymorphisms and illuminate how one schizophrenia-associated variant affects neurodevelopment. Science , this issue p. [561][1] [1]: /lookup/doi/10.1126/science.aay3983

Genome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours

Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci (P < 1×10−8), respectively. High genetic correlations are observed between sedentary behaviours and neurological traits, including education and body mass index (BMI). Two-sample Mendelian randomization (MR) analysis estimates a causal effect between 1.5 hour increase in television watching and CAD (OR 1.44, 95%CI 1.25–1.66, P = 5.63 × 10−07), that is partially independent of education and BMI in multivariable MR analyses. This study finds independent observational and genetic support for the hypothesis that increased sedentary behaviour by leisure television watching is a risk factor for CAD.