Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related risk loci, genes, and pathways. We first focused on CIDP, and 516 CIDP cases and 403,545 controls were included in the GWAS analysis. We also investigated genetic risk for inflammatory polyneuropathy (IP), in which we performed a GWAS study using FinnGen data and combined the results with GWAS from the UK Biobank using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. Stratified analyses by gender were performed. Mendelian randomization (MR), colocalization, and transcriptome-wide association study (TWAS) analyses were performed to identify associated genes. Gene-set analyses were conducted to identify associated pathways. We identified one genome-wide significant locus at 20q13.33 for CIDP risk among women, the top variant located at the intron region of gene CDH4. Sex-combined MR, colocalization, and TWAS analyses identified three candidate pathogenic genes for CIDP and five genes for IP. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. Sex-stratified analyses identified three genes for IP among males and two genes for IP among females. Our study identified suggestive risk genes and pathways for CIDP and IP. Functional analyses should be conducted to further confirm these associations.
Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.
Multiple sclerosis (MS) susceptibility is characterized by maternal parent-of-origin effects and increased female penetrance.In 7796 individuals from 1797 MS families (affected individuals n 5 2954), we further implicate epigenetic modifications within major histocompatibility complex (MHC) class II haplotypes as mediating these phenomena.Affected individuals with the main MS-associated allele HLA-DRB1 * 15 had a higher female-to-male ratio versus those lacking it (P 5 0.00023).Distorted transmission of MHC haplotypes by both parent-of-origin and gender-of-affected-offspring was most evident in the maternal HLA-DRB1 * 15 transmission to affected female offspring (OR 5 3.31, 95% CI 5 2.59 -4.24) contrasting with similarity among maternal transmission to affected male offspring (OR 5 2.13, 95% CI 5 1.44 -3.14), paternal transmissions to affected female (OR 5 2.14, 95% CI 5 1.64 -2.78) and male (OR 5 2.16, 95% CI 5 1.37 -3.39) offspring.Significant parent-of-origin effects were observed in affected females (maternal: P 5 9.33 3 10 242 ; paternal: P 5 1.12 3 10 215 ; comparison: P 5 0.0014), but not in affected males (maternal: P 5 6.70 3 10 28 ; paternal: P 5 2.54 3 10 26 ; comparison: P 5 0.95).Conditional logistic regression analysis revealed further differential risk of HLA diplotypes.Risks for HLA-DRB1 * 15 and likely for other HLA-DRB1 haplotypes were restricted by (i) parent-of-origin, (ii) gender-of-offspring and (iii) trans epistasis in offspring.These findings may illuminate the gender bias characterizing autoimmunity overall.They raise questions about the concept of restricted antigen presentation in autoimmunity and suggest that gender-specific epigenetic interactions may be the driving forces behind the MHC haplotypic associations.Haplotype-specific epigenetic modifications at MHC class II and their decay appear to be at the heart of MS pathogenesis and inheritance of risk, providing the focus for gene -environment interactions that determine susceptibility and resistance.
Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18–31 (beta coefficients ranged from 0.02–0.06, p-values ranged from 10−6–10−12), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective.
Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2–21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.
Abstract Objective Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related risk loci , genes and pathways. Methods To increase power, we first included all patients with a diagnosis of inflammatory polyneuropathy (IP) as cases. We performed a GWAS study using FinnGen R10 individual data and combined the results with GWAS from UK biobank (UKBB) using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. The second GWAS focused on CIDP patients and a total of 516 CIDP cases and 403,545 controls were included in the analysis. Stratified analyses by gender were also performed for both IP and CIDP. We performed gene-level analyses using transcriptome-wide mendelian randomization (TWMR) analysis, colocalization analysis, transcriptome-wide association study (TWAS) using S-PrediXcan and MAGMA to identify genes associated with IP and CIDP. Gene-set analyses were conducted using MAGMA to identify pathways that are related to IP and CIDP. Results In GWAS study, we identified one genome-wide significant loci at 20q13.33 for CIDP risk among women; the top variant located at the intron region of gene CDH4 . TWMR, colocalization and S-PrediXcan analyses identified DGKQ, GLDC, IDUA, SLAMF9 and TMEM175 as candidate pathogenic genes for IP; genes DIRAS1, GNG7 , and SLC39A3 for CIDP; genes DIRAS1, DCTN1 , and ME1 for IP among males; and genes DIRAS1 and ME1 for IP among women. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. Conclusion Our study identified suggestive risk genes and pathways for IP and CIDP. Functional analysis should be conducted to further confirm these associations.
Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. Consequently, we performed whole-genome sequencing of HD and control subjects from four independent families in whom the major European HD haplotype segregates with the disease. Analysis of the full-sequence-based HTT haplotype indicated that these four families share a common ancestor sufficiently distant to have permitted the accumulation of family-specific variants. Confirmation of new CAG-expansion mutations on this haplotype suggests that unlike most founders of human disease, the common ancestor of HD-affected families with the major haplotype most likely did not have HD. Further, availability of the full sequence data validated the use of SNP imputation to predict the optimal variants for capturing heterozygosity in personalized allele-specific gene-silencing approaches. As few as ten SNPs are capable of revealing heterozygosity in more than 97% of European HD subjects. Extension of allele-specific silencing strategies to the few remaining homozygous individuals is likely to be achievable through additional known SNPs and discovery of private variants by complete sequencing of HTT. These data suggest that the current development of gene-based targeting for HD could be extended to personalized allele-specific approaches in essentially all HD individuals of European ancestry.
Apolipoprotein E (APOE) e4 is the strongest genetic risk factor for Alzheimer's disease (AD). Although its association with AD is well-established, the impact of APOE e4 on human brain cell function remains unclear. Here we investigated the effects of APOE e4 on brain cell types derived from human induced pluripotent stem cells and human APOE targeted replacement mice. Global transcriptomic profiles showed that APOE e4 is associated with dysregulation of cholesterol homeostasis in human but not mouse glia. Elevated matrisome signaling in APOE e4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted APOE e4 glia and AD post-mortem brains. In vitro study showed that isogenic APOE e4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE e4 glia also secrete higher levels of proinflammatory chemokines/cytokines, indicative of glial activation. Thus, APOE e4 induces human glia-specific dysregulation that may initiate AD risk.
ABSTRACT INTRODUCTION The National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer’s disease (AD). METHODS Recruitment focused on families with two living affected siblings and a third first degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained as was neuropathology, when possible. APOE genotypes, genome-wide SNP arrays and sequencing was completed in the majority of families. RESULTS A wide range in the age-at-onset in many large families was related to APOE genotype, but not in all. Variants typically associated with early-onset AD and frontotemporal dementia were also found. DISCUSSION The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 126 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)