Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in ...astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV‐1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno‐associated virus‐based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV‐inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV‐1 proviral editing by CRISPR/Cas9. Latently HIV‐1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV‐1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV‐1 proviruses in astrocyte reservoirs.
Main Points
There is a growing interest in astrocytes as reservoirs for HIV‐1 in the brain.
We identify a new vector (AAV9P1) for targeting human astrocytes and show the use of AAV9P1 for inactivation of latent HIV‐1 proviruses by CRISPR/Cas9 gene editing.
Abstract
Aims
Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced ...PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG).
Methods and results
In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose–response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74).
Conclusion
We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.
The RBL2 locus has been associated with intelligence and educational attainment but not with a monogenic disorder to date. RBL2 encodes p130, a member of the retinoblastoma protein family, which is ...involved in mediating neuron survival and death. Previous studies on p130 knockout mice revealing embryonic death and impaired neurogenesis underscore the importance of RBL2 in brain development. Exome sequencing in two siblings with severe intellectual disability, stereotypies and dysmorphic features identified biallelic loss‐of‐function variants c.556C>T, p.(Arg186Ter) and a deletion of exon 13–17 in RBL2 (NM_005611.3), establishing RBL2 as a candidate gene for an autosomal recessive neurodevelopmental disorder.
Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered ...replication cohorts. The previous largest GWAS identified
nd
loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.
A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).
The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P<5x10
). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published
variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)
=0.477(0.203), P
=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N
=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported
locus (rs983361:β(SE)
=0.720(0.122), P
=3.13x10
) and a novel
locus (rs4698412:β(SE)
=-0.526(0.096), P
=4.41x10
).
Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of
as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used ...2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR.BACKGROUND AND OBJECTIVESThe role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR.We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 95% CI) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI.METHODSWe used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 95% CI) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI.Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 0.70-0.97, p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 0.55-0.92) and cases with shorter disease duration (≤7 years, ORIVW 0.75 0.62-0.91). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 0.74-0.99, p = 0.032) than men (ORIVW 0.92 0.80-1.04, p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association.RESULTSSummary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 0.70-0.97, p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 0.55-0.92) and cases with shorter disease duration (≤7 years, ORIVW 0.75 0.62-0.91). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 0.74-0.99, p = 0.032) than men (ORIVW 0.92 0.80-1.04, p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association.Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.DISCUSSIONUsing an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.
Objective
The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of ...individual‐level genetic data available.
Methods
We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome‐wide association study meta‐analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene‐based analyses and functional enrichment analyses.
Results
A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error SE = 0.022, p = 0.013). Although no single locus reached genome‐wide significance, MAGMA gene‐based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow‐sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.
Interpretation
The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high‐risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278
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