Sunday, August 7, 2022

Genetic Link Between Parkinson’s And Schizophrenia

Study Changes The Idea Of The Link Between Parkinsons Disease And Schizophrenia

Link found between schizophrenia, bipolar disorder

PD is currently the fastest-growing neurological disease in the world. It is a neurodegenerative condition most common in people over 60 years of age. Cardinal motor symptoms include shaking, stiffness, and slow movement. Approximately 15,000 patients are currently undergoing PD diagnosis in Finland.

In Parkinsons disease, the neurons found in the substantia nigra steadily degenerate into the mid-brain. It is due to a deficiency in a neurotransmitter named dopamine. As for schizophrenia, the amount of dopamine rises in certain parts of the brain. Also, PD symptoms can be relieved with dopamine receptor agonists. Schizophrenia is commonly treated with dopamine receptor antagonists.

Association Between Dbh And Pd

A meta-analysis of the association between DBH polymorphisms and PD risk included seven studies involving a total of 3482 cases and 4086 controls, including four for rs1611115 , two for rs2519152 , and one for rs732833 . The analysis results showed that no associations between a collection of all three DBH polymorphisms with susceptibility to PD was observed in three genetic patterns . From the viewpoint of each DBH locus, a lack of association was also found between the polymorphisms of two loci and PD risk in more than one study . In subgroup analysis by ethnicity, no association between the rs1611115 polymorphism and PD development was observed among Caucasians , but the association was statistically significant in Asians, represented by only one study under the allelic and dominant genetic models . In addition, the rs732833 polymorphism, which presented in only one study, was also not associated with the risk of PD under any of the three genetic models . In summary, the above results suggested that no associations exists between the DBH rs1611115, rs2519152, and rs732833 polymorphisms individually or in combination with the risk of developing PD.

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Data revealed that dopamine-producing neurons had a total of 71,022 TNEs, 33% of which were active enhancers regulatory sites that work like switches to turn on the expression of specific genes in neurons. Many of these TNEs had never been described in the brain before, and most were exclusively expressed in human dopamine neurons, and not detected in other types of nerve cells.

Interestingly, a high percentage of the TNEs described were enriched in genetic variants of several neuropsychiatric disorders, including not only Parkinsons, but also schizophrenia, bipolar disorder, and addiction.

This work suggests that noncoding RNAs active in dopamine neurons are a surprising link between genetic risk, Parkinsons and psychiatric disease, Scherzer said. Based on this connection we hypothesize that the risk variants might fiddle with the gene switches of dopamine-producing brain cells.

Scherzers team has compiled all the findings in a publicly available database called BRAINcode they hope will contribute to advancing studies focused on defining disease targets and biomarkers for Parkinsons and other neuropsychiatric disorders.

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Sensitivity Analysis And Publication Bias

Sensitivity analysis showed that the pooled ORs were not significantly altered for the DBH rs1611115, 5-Ins/Del, and rs1108580 polymorphisms presenting in more than three studies on AD, PD and SCZ when all the included studies were excluded one by one, which indicated that our results were robust and reliable . According to the shapes of Beggs funnel plots created by the trim and fill method, no asymmetric signal was observed under the allelic model . Further quantitative tests also suggested no publication bias for these SNPs and the risks of AD, PD and SCZ .

Table 5.

Reported results of Beggs test to assess risk of publication bias on DBH polymorphisms and Alzheimers disease, Parkinsons disease, and schizophrenia. Note: P -Begg: P value of the Beggs test

Fig. 3.

Funnel plot for the allelic model to analyze the publication bias of the association between the DBH 5-Ins/Del polymorphism and SCZ risk by the trim and fill method.

Association Of Dbh With Diseases With Neurodegenerative Features Including Ad Pd And Scz

The Parkinson

In this systematic analysis, a total of 41 studies involving 10506 cases and 15083 controls, including seven on AD , seven on PD , and twenty-seven on SCZ , were used in combination to investigate the association between a combination of all the available DBH polymorphisms and the development of diseases with neurodegenerative features, including AD, PD and SCZ. The combined results showed a lack of association between them under three genetic models . In subgroup analysis by ethnicity, no associations of the sixteen DBH polymorphisms with the risks of these three diseases were found among either Caucasians or Asians . In summary, the previously reported DBH polymorphisms did not have any cumulative effect on the susceptibility to diseases with neurodegenerative features, including AD, PD and SCZ.

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Genetic Causes Of Schizophrenia

Many genes play a role in your odds of getting schizophrenia. A change to any of them can do it. But usually, itâs several small changes that add up and lead to a higher risk. Doctors arenât sure how genetic changes lead to schizophrenia. But theyâve found that people who have the disorder may be more likely to have problems in their genes that may interfere with brain development.

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Expression And Methylation Quantitative Trait Analyses

Data for this aspect of analyses were made possible through collaborative efforts of the North American and United Kingdom Brain Expression Consortia . Frozen frontal cortex and cerebellar samples were obtained from > 399 self-reported European ancestry samples without determinable neuropatholgical evidence of disease. Genomic DNA was extracted with phenolchloroform. Bisulfite converted DNA and assayed at > 27 000 sites on the Illumina Infinium HumanMethylation27 BeadChips. MRNA expression levels were assayed using Illumina HumanHT-12 v3 Expression Beadchips. In brief, individual probes were excluded from analyses if the P-value for detection was > 0.01 or there was < 95% completeness of data per probe, and samples were excluded if < 95% of probes were detected. Probes were also removed if an analyzed SNP was within the probe or the probe mapped ambiguously to multiple locations in the genome. Expression data were cubic spline normalized and log 2-transformed prior to analyses.

Each tissue sample was genotyped using the Illumina HumanHap550 v3, Human610-Quad v1 or Human660W-Quad v1 Infinium Beadchips, shared SNPs were extracted prior to QC and imputation. Standard GWAS quality control was undertaken with inclusion criteria such as: minimum call rate 95% for both participants and SNPs, minor allele frequency > 0.01, HWE > 1E7, no first-degree relatives in the sample collection and European ancestry confirmed by multidimensional scaling analyses.

Current Methods For Genetic Analysis Of Complex Disorder

Scientists demonstrate link between genetic defect and brain changes in schizophrenia

Available methods generally rely on the analysis of DNA markers in subject to determine whether the distribution of marker alleles in some way predicts the presence of disease. Some studies consider DNA variations within or near candidate gene. Many groups are now examining maps of the DNA markers throughout the genome to identify chromosomal regions likely to contain loci that have a major influence on susceptibility. These studies rely on the phenomenon of linkage, as exemplified by the fact that when ill parent transmits a disease-causing allele to children, numerous alleles at nearby loci are also transmitted because no recombination event has occurred in the region .

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The Basic Genetics Of Schizophrenia

Schizophrenia aggregates in the families with no known familial subtypes. Twin and adoption studies have shown that this familiarity is explained predominantly by genetic factors, with estimates of genetic contribution ranging from 60 to 80%. However, these data do not follow a simple recessive or dominant pattern. If it were simple recessive, the frequency in children of two schizophrenic parents would be 100%, but is actually under 40% if it were simple dominant, 50% of the offspring of one schizophrenic parent would be affected and each person with schizophrenia would have one ill parent . Moreover, the prevalence in offspring is too low to be consistent with the high monozygotic twin concordance rate. Thus, the genetic effect is not completely penetrant indicating that many relatives of people with schizophrenia may carry silent genetic susceptibility. Detail of the risk of illness among relatives with schizophrenia is shown in . A further complication is the epidemiological evidence that, while a high population prevalence has been maintained, the reproductive rate of people with schizophrenia is low.

Dopamine Dysfunction In Schizophrenia: From Genetic Susceptibility To Cognitive Impairment

10.4 Dopamine Dysfunction in Schizophrenia: From Genetic Susceptibility to Cognitive Impairment
Oxford University Press

This chapter provides an overview of the causes and effects of dopamine dysfunction in schizophrenia. In doing so, it summarizes historical perspectives and our current scientific knowledge about the susceptibility genes, neural system anomalies, and cognitive symptoms that link the disorder to disturbances in dopamine neurotransmission.

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Base And Target Data: Quality Control And Exclusions

Blood samples from 488,366 UK Biobank participants were genotyped using the UK BiLEVE array or the UK Biobank axiom array. Further details on the genotyping and quality control can be found on the UK Biobank website . In the current study, SNPs were removed if they had missingness> 0.02 and MAF< 0.01. Samples were removed from the dataset if they had missingness> 0.01. We used a subset of European ancestry inferred individuals, defined using 4-means clustering applied to the first two PCs of the genotype data, because PRS are typically underpowered when applied to target samples of a different global ancestry to that of the base data using current PRS methods. Confirming this to be the case here, we repeated the analysis of the top 20 PRStrait associations in the full cohort including 20,798 non-European ancestry inferred individuals and observed less significant PRStrait associations in 12 of the 20 results despite the substantial increase in sample size . One of each pair of related individuals were removed using a relatedness criterion KING coefficient< 0.088. Exclusions based on heterozygosity and missingness were implemented according to UK Biobank recommendations . Samples were removed if they were discordant for sex. SNPs deviating from Hardy-Weinberg equilibrium were removed at a threshold of P< 108. This QC process resulted in a data set of 560,173 SNPs and 386,192 samples available for analysis.

How Is Anhedonia Diagnosed

CRISPR may help neuroscientists unlock genetics of psychiatric disease ...

If you think youre experiencing anhedonia, consider reaching out to a healthcare or mental health professional. Blood tests or other medical tests may be done to rule out any other potential causes of your symptoms. You may also be given a series of tests, including a psychological evaluation or assessment, to determine if youre experiencing symptoms of a mental health condition.

If its determined that you may be experiencing anhedonia, one or more questionnaires may be used to determine which category of anhedonia youre experiencing. This could include the Chapman physical anhedonia scale or the Chapman social anhedonia scale .

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Main Characteristics Of The Included Studies

Table 1 presents the main characteristics of the 41 studies utilized in this meta-analysis. These studies were published from 1996 to 2016. Among them, 25 studies involved Caucasian populations , and 16 studies involved Asian populations . Additionally, two diagnostic criteria were used among the AD studies included , two criteria were used for PD studies and Standard for Second National conference on Cone Diseases), and three criteria were used for SCZ studies . Using the methodological quality assessment according to NOS, all the included studies had scores greater than six and were considered high-quality . Detailed genotype data from each original study are shown in Table S1.

Table 1.

Main characteristics of studies included in the meta-analysis. NA: Not available HWE: Hardy-Weinberg equilibrium CERAD: Consortium to Establish a Registry for Alzheimers Disease NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association UK-PDSBB: UK Parkinsons Disease Society Brain Bank Clinical Diagnostic Criteria DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders-III-R DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders-IV-TR BPRS: Brief Psychiatric Rating Scale CGI: Clinical Global Impression ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th revision

Table 2.

Quality assessment scheme for the included literatures

How The Search Began

Several strategies are available in the search for the study goal. The search for relevant DNA sequence variations can either focus on specific genes with known physiologically relevant products or can precede in a hypothesis-free manner in which each gene is considered in an a priori way as a putative candidate. The preferred search strategy for the first approach involves association studies with candidate genes, which were selected on the basis of the current pathophysiological knowledge for the second approach, linkages studies are required. The latter approach was enormously successful in the study of monogenic disorders.

The systematic hypothesis-free genome-wide strategy required the following: systems of positional DNA markers placed densely on the whole genome and sample of genetically informative families each with more than one affected case . Unfortunately, it has been shown that this strategy did not guarantee quick success for complex disorders as contrast with monogenic diseases

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Transcriptomic Atlases For Ldsc

We first applied linkage disequilibrium score regression in specifically expressed genes to identify disease-relevant tissues and cell types by analyzing gene expression data together with GWAS summary statistics . LDSC-SEG identifies tissues in which genes with increased expression are enriched in single-nucleotide polymorphisms that tag a large amount of heritability. Data for LDSC-SEG was prepared as described earlier . Gene expression data from the following sources were analyzed: 1) RNA sequencing read counts from Genotype-Tissue Expression v6p . Genes for which fewer than four samples had at least one read count per million, as well as samples for which fewer than 100 genes had at least one read count per million were removed. 2) GeneChip expression array data from mouse forebrain sorted cells downloaded in the Gene Expression Omnibus . 3) Publicly available gene expression data from the ImmGen project downloaded in GEO . A p value below 9.43E-04 , 0.017 , and 1.71E-04 was considered statistically significant after the Bonferroni correction for analysis using the GTEx, GSE9566 and ImmGen data respectively.

Regional And National Records

How are Schizophrenia and Parkinson’s related?

The researchers studied the medical history of 3,045 individuals treated for Parkinsons disease in southwest Finland between 2004 and 2019. 22,189 patients entered the Finnish national registry between 1996 and 2015.

They contrasted the prevalence of pre-existing schizophrenia diagnoses in Parkinsons patients.

Nationally, the prevalence of schizophrenia spectrum disorders in individuals with Parkinsons disease was 1.5 percent compared to 1.31 percent among the controls.

Regionally, the prevalence was 0.76% in those with Parkinsons disease in comparison to 0.16% for the controls.

There are obvious differences in prevalence between national and regional results. But, this indicates that having schizophrenia increases a persons chance of developing Parkinsons.

Researchers suggest that increased risk can result from prolonged use of medications. These medications block dopamine receptors, known as dopamine receptor antagonists.

Drugs can change the brains dopamine system. It improves a persons risk of having Parkinsons disease.

Alternatively, over time, schizophrenia may directly damage the dopamine system. This makes a person more vulnerable to Parkinsons disease.

We need more studies to investigate whether the severity of psychotic symptoms or the type or dosage of antipsychotic drugs impacts the risk of , say the researchers in their paper.

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Differential Expression In Patients And Controls

To determine whether the identified risk genes were differentially expressed in tissues from patients with ALS or schizophrenia compared with healthy controls, we analyzed the gene expression of the target genes in whole blood from 233 ALS patients and 508 controls , and neurons from human induced pluripotent stem cell in 12 schizophrenia patients and 12 controls . Data were prepared and analyzed using GEO2R , and a p value below 0.05 was considered significant after adjusting for multiple testing.

The Role Of Brain Chemistry And Structure In Schizophrenia

Scientists are looking at possible differences in brain structure and function in people with and people without schizophrenia. In people with schizophrenia, they found that:

  • Spaces in the brain, called ventricles, were larger.
  • Parts of the brain that deal with memory, known as the medial temporal lobes, were smaller.
  • There were fewer connections between brain cells.

People with schizophrenia also tend to have differences in brain chemicals called neurotransmitters. These control communication within the brain.

Studies show that these neurotransmitters are either too active or not active enough in people with schizophrenia.

Doctors also believe the brain loses tissue over time. And imaging tools, like PET scans and MRIs, show that people who have schizophrenia have less âgray matterâ — the part of the brain that contains nerve cells — over time.

Studies of brain tissue in people with schizophrenia after death even show that their brain structure is often different than it was at birth.

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