Contribution of rare variant associations to neurodegenerative disease presentation

AbstractGenetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

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Germline Genetic Factors Influence Outcome of Interferon Alpha Therapy in Polycythemia Vera

Blood ◽

10.1182/blood.2020005792 ◽

2020 ◽

Author(s):

Roland Jäger ◽

Heinz Gisslinger ◽

Elisabeth Fuchs ◽

Edith Bogner ◽

Jelena D. Milosevic Feenstra ◽

...

Keyword(s):

Polycythemia Vera ◽

Interferon Alpha ◽

Genetic Factors ◽

Myeloproliferative Neoplasms ◽

Association Studies ◽

Study Cohort ◽

Molecular Response ◽

Genome Wide Association Studies ◽

Association Analyses ◽

Genome Wide

Interferon alpha (IFNα) based therapies can induce hematologic and molecular responses in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have previously been implicated in differential drug response. We addressed the effect of common germline polymorphisms on hematologic and molecular response (HR/MR) in PV therapy within the PROUD-PV and CONTINUATION-PV studies including 122 patients with PV receiving ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over 36 months follow-up did not reveal any associations at genome-wide significance. Further, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during therapy of myeloproliferative neoplasms. While we did not observe any association of IFNL4 polymorphisms with HR in our study cohort, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair including the protein-coding variants rs368234815/rs117648444) on MR (p=3.91x10-4; OR=10.80; 95%CI:[2.39-69.97]) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of PV patients based on IFNL4 functionality may allow for optimizing patient management during IFNα treatment.

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A permutation method for detecting trend correlations in rare variant association studies

Genetics Research ◽

10.1017/s0016672319000120 ◽

2019 ◽

Vol 101 ◽

Author(s):

Lifeng Liu ◽

Pengfei Wang ◽

Jingbo Meng ◽

Lili Chen ◽

Wensheng Zhu ◽

...

Keyword(s):

Rare Variant ◽

Type I Error ◽

Rare Variants ◽

Association Studies ◽

Complex Diseases ◽

Type I ◽

Phenotypic Variance ◽

Rare Variant Association ◽

Significance Level ◽

Association Analyses

Abstract In recent years, there has been an increasing interest in detecting disease-related rare variants in sequencing studies. Numerous studies have shown that common variants can only explain a small proportion of the phenotypic variance for complex diseases. More and more evidence suggests that some of this missing heritability can be explained by rare variants. Considering the importance of rare variants, researchers have proposed a considerable number of methods for identifying the rare variants associated with complex diseases. Extensive research has been carried out on testing the association between rare variants and dichotomous, continuous or ordinal traits. So far, however, there has been little discussion about the case in which both genotypes and phenotypes are ordinal variables. This paper introduces a method based on the γ-statistic, called OV-RV, for examining disease-related rare variants when both genotypes and phenotypes are ordinal. At present, little is known about the asymptotic distribution of the γ-statistic when conducting association analyses for rare variants. One advantage of OV-RV is that it provides a robust estimation of the distribution of the γ-statistic by employing the permutation approach proposed by Fisher. We also perform extensive simulations to investigate the numerical performance of OV-RV under various model settings. The simulation results reveal that OV-RV is valid and efficient; namely, it controls the type I error approximately at the pre-specified significance level and achieves greater power at the same significance level. We also apply OV-RV for rare variant association studies of diastolic blood pressure.

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Rare variant enriched identity-by-descent enables the detection of distant relatedness and older divergence between populations

10.1101/2020.05.05.079541 ◽

2020 ◽

Author(s):

Amol C. Shetty ◽

Jeffrey O’Connell ◽

Braxton D. Mitchell ◽

Timothy D. O’Connor ◽

◽

...

Keyword(s):

Rare Variant ◽

Human Population ◽

Large Scale ◽

Genetic Relatedness ◽

Rare Variants ◽

Association Studies ◽

Common Variants ◽

Identity By Descent ◽

Association Analyses ◽

Scale Population

AbstractMotivationThe global human population has experienced an explosive growth from a few million to roughly 7 billion people in the last 10,000 years. Accompanying this growth has been the accumulation of rare variants that can inform our understanding of human evolutionary history. Common variants have primarily been used to infer the structure of the human population and relatedness between two individuals. However, with the increasing abundance of rare variants observed in large-scale projects, such as Trans-Omics for Precision Medicine (TOPMed), the use of rare variants to decipher cryptic relatedness and fine-scale population structure can be beneficial to the study of population demographics and association studies. Identity-by-descent (IBD) is an important framework used for identifying these relationships. IBD segments are broken down by recombination over time, such that longer shared haplotypes give strong evidence of recent relatedness while shorter shared haplotypes are indicative of more distant relationships. Current methods to identify IBD accurately detect only long segments (> 2cM) found in related individuals.AlgorithmWe describe a metric that leverages rare-variants shared between individuals to improve the detection of short IBD segments. We computed IBD segments using existing methods implemented in Refined IBD where we enrich the signal using our metric that facilitates the detection of short IBD segments (<2cM) by explicitly incorporating rare variants.ResultsTo test our new metric, we simulated datasets involving populations with varying divergent time-scales. We show that rare-variant IBD identifies shorter segments with greater confidence and enables the detection of older divergence between populations. As an example, we applied our metric to the Old-Order Amish cohort with known genealogies dating 14 generations back to validate its ability to detect genetic relatedness between distant relatives. This analysis shows that our method increases the accuracy of identifying shorter segments that in turn capture distant relationships.ConclusionsWe describe a method to enrich the detection of short IBD segments using rare-variant sharing within IBD segments. Leveraging rare-variant sharing improves the information content of short IBD segments better than common variants alone. We validated the method in both simulated and empirical datasets. This method can benefit association analyses, IBD mapping analyses, and demographic inferences.

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Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury

Cells ◽

10.3390/cells10123460 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3460

Author(s):

Larry N. Singh ◽

Shih-Han Kao ◽

Douglas C. Wallace

Keyword(s):

Mitochondrial Dna ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Genetic Factors ◽

Mitochondrial Genetics ◽

Dna Variation ◽

Parkinson’S Diseases ◽

And Function ◽

The Impact

Neurodegenerative disorders that are triggered by injury typically have variable and unpredictable outcomes due to the complex and multifactorial cascade of events following the injury and during recovery. Hence, several factors beyond the initial injury likely contribute to the disease progression and pathology, and among these are genetic factors. Genetics is a recognized factor in determining the outcome of common neurodegenerative diseases. The role of mitochondrial genetics and function in traditional neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, is well-established. Much less is known about mitochondrial genetics, however, regarding neurodegenerative diseases that result from injuries such as traumatic brain injury and ischaemic stroke. We discuss the potential role of mitochondrial DNA genetics in the progression and outcome of injury-related neurodegenerative diseases. We present a guide for understanding mitochondrial genetic variation, along with the nuances of quantifying mitochondrial DNA variation. Evidence supporting a role for mitochondrial DNA as a risk factor for neurodegenerative disease is also reviewed and examined. Further research into the impact of mitochondrial DNA on neurodegenerative disease resulting from injury will likely offer key insights into the genetic factors that determine the outcome of these diseases together with potential targets for treatment.

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Therapeutic Potential of α-Crystallins in Retinal Neurodegenerative Diseases

Antioxidants ◽

10.3390/antiox10071001 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1001

Author(s):

Ashutosh S. Phadte ◽

Zachary B. Sluzala ◽

Patrice E. Fort

Keyword(s):

Cell Death ◽

Animal Models ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Therapeutic Potential ◽

Loss Of Function ◽

Neuronal Viability ◽

Current Review ◽

Progressive Loss ◽

Apoptotic Activity

The chaperone and anti-apoptotic activity of α-crystallins (αA- and αB-) and their derivatives has received increasing attention due to their tremendous potential in preventing cell death. While originally known and described for their role in the lens, the upregulation of these proteins in cells and animal models of neurodegenerative diseases highlighted their involvement in adaptive protective responses to neurodegeneration associated stress. However, several studies also suggest that chronic neurodegenerative conditions are associated with progressive loss of function of these proteins. Thus, while external supplementation of α-crystallin shows promise, their potential as a protein-based therapeutic for the treatment of chronic neurodegenerative diseases remains ambiguous. The current review aims at assessing the current literature supporting the anti-apoptotic potential of αA- and αB-crystallins and its potential involvement in retinal neurodegenerative diseases. The review further extends into potentially modulating the chaperone and the anti-apoptotic function of α-crystallins and the use of such functionally enhanced proteins for promoting neuronal viability in retinal neurodegenerative disease.

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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

Nature Communications ◽

10.1038/s41467-021-24563-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lucas D. Ward ◽

Ho-Chou Tu ◽

Chelsea B. Quenneville ◽

Shira Tsour ◽

Alexander O. Flynn-Carroll ◽

...

Keyword(s):

Bile Duct ◽

Extrahepatic Bile Duct ◽

Association Studies ◽

Missense Variant ◽

Deficiency Anemia ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Extrahepatic Bile Duct Cancer ◽

Hepatocellular Damage ◽

Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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Genetic architecture of schizophrenia: a review of major advancements

Psychological Medicine ◽

10.1017/s0033291720005334 ◽

2021 ◽

pp. 1-10

Author(s):

Sophie E. Legge ◽

Marcos L. Santoro ◽

Sathish Periyasamy ◽

Adeniran Okewole ◽

Arsalan Arsalan ◽

...

Keyword(s):

Genetic Architecture ◽

Association Studies ◽

Copy Number Variants ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genetic Loci ◽

Significant Enrichment ◽

High Heritability ◽

Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

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Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Genes ◽

10.3390/genes12060934 ◽

2021 ◽

Vol 12 (6) ◽

pp. 934

Author(s):

Donato Gemmati ◽

Giovanna Longo ◽

Eugenia Franchini ◽

Juliana Araujo Silva ◽

Ines Gallo ◽

...

Keyword(s):

At Risk ◽

Stop Codon ◽

Association Studies ◽

Premature Stop Codon ◽

Large Family ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Gene Markers ◽

Inherited Thrombophilia ◽

Fv Leiden

Inherited thrombophilia (e.g., venous thromboembolism, VTE) is due to rare loss-of-function mutations in anticoagulant factors genes (i.e., SERPINC1, PROC, PROS1), common gain-of-function mutations in procoagulant factors genes (i.e., F5, F2), and acquired risk conditions. Genome Wide Association Studies (GWAS) recently recognized several genes associated with VTE though gene defects may unpredictably remain asymptomatic, so calculating the individual genetic predisposition is a challenging task. We investigated a large family with severe, recurrent, early-onset VTE in which two sisters experienced VTE during pregnancies characterized by a perinatal in-utero thrombosis in the newborn and a life-saving pregnancy-interruption because of massive VTE, respectively. A nonsense mutation (CGA > TGA) generating a premature stop-codon (c.1171C>T; p.R391*) in the exon 6 of SERPINC1 gene (1q25.1) causing Antithrombin (AT) deficiency and the common missense mutation (c.1691G>A; p.R506Q) in the exon 10 of F5 gene (1q24.2) (i.e., FV Leiden; rs6025) were coinherited in all the symptomatic members investigated suspecting a cis-segregation further confirmed by STR-linkage-analyses [i.e., SERPINC1 IVS5 (ATT)5–18, F5 IVS2 (AT)6–33 and F5 IVS11 (GT)12–16] and SERPINC1 intragenic variants (i.e., rs5878 and rs677). A multilocus investigation of blood-coagulation balance genes detected the coexistence of FV Leiden (rs6025) in trans with FV HR2-haplotype (p.H1299R; rs1800595) in the aborted fetus, and F11 rs2289252, F12 rs1801020, F13A1 rs5985, and KNG1 rs710446 in the newborn and other members. Common selected gene variants may strongly synergize with less common mutations tuning potential life-threatening conditions when combined with rare severest mutations. Merging classic and newly GWAS-identified gene markers in at risk families is mandatory for VTE risk estimation in the clinical practice, avoiding partial risk score evaluation in unrecognized at risk patients.

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Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

International Journal of Molecular Sciences ◽

10.3390/ijms22094334 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4334

Author(s):

Katrina Albert ◽

Jonna Niskanen ◽

Sara Kälvälä ◽

Šárka Lehtonen

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Induced Pluripotent Stem Cells ◽

Glial Cells ◽

Pluripotent Stem Cells ◽

Cell Types ◽

Human Ipscs ◽

Induced Pluripotent

Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.

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HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry

Translational Psychiatry ◽

10.1038/s41398-021-01322-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bettina Konte ◽

James T. R. Walters ◽

Dan Rujescu ◽

Sophie E. Legge ◽

Antonio F. Pardiñas ◽

...

Keyword(s):

Genetic Factors ◽

Risk Allele ◽

Effect Sizes ◽

European Ancestry ◽

Treatment Resistant ◽

Allele Distribution ◽

Association Analyses ◽

Local Ancestry ◽

Risk Variants ◽

Effective Medication

AbstractThe atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

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