Theory Autism & Schizophrenia: Genetic Associations

[Intellau_Celistic]

The two conditions known as Autistic Spectrum Disorder(ASD) and Schizophrenic Spectrum Disorder(SSD) are closely associated, genetically-speaking.

ASD:

NINDS : 52 Autistic disorder (sometimes called autism or classical ASD) is the most common condition in a group of developmental disorders known as the autism spectrum disorders (ASDs). Autistic children have difficulties with social interaction, display problems with verbal and nonverbal communication, and exhibit repetitive behaviors or narrow, obsessive interests. These behaviors can range in impact from mild to disabling. Autism varies widely in its severity and symptoms and may go unrecognized, especially in mildly affected children or when more debilitating handicaps mask it. Scientists aren’t certain what causes autism, but it’s likely that both genetics and environment play a role. Autism spectrum disorder is diagnosed based on symptoms, signs, and other testing according to the Diagnostic and Statistical Manual V, a guide created by the American Psychiatric Association to diagnose mental disorders. Children should be screened for developmental delays during periodic checkups and specifically for autism at 18- and 24-month well child visits.

Autism Spectrum Disorder disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials

www.malacards.org

SSD:

UniProtKB/Swiss-Prot : 71 A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder.

https://www.malacards.org/card/schizophrenia?search=Schizophrenia

ASD and SSD are both known to cause cognitive impairments and sensory problems/psychosis...

I'll focus on Processing Speed for this thread:

What is Processing Speed?​

When describing Processing Speed in my reports, I write:


Processing Speed measures the speed and accuracy of visual identification, decision making, and decision implementation.


There are three key components of this statement: 1) visual identification, 2) decision making, and 3) decision implementation. Simply put, processing speed involves the ability to identify the task at hand, recognize the decision that needs to be made, and make the decision.


Students who excel at processing speed are able to work quickly on cognitive and academic tasks. Usually they are among the first students to finish a test or to complete homework assignments. Determining a student’s processing speed gives us insight into how efficiently he or she is able to complete such tasks. As we’ll see below, however, students who work quickly may also experience other variables that contribute to their speed, some that aren’t necessarily positive.

How is it Calculated?​

The Processing Speed index score is calculated using two subtests: Coding and Symbol Search. This is true for both the WISC-V (for children and adolescents) and the WAIS-IV (for adults).


The Coding subtest requires the student to view a series of numbers written in rows on a page. The student then draws a corresponding symbol under each number. The student is given two minutes to complete as many symbols as possible. The student is awarded one point for each correctly drawn symbol. The student is not penalized for incorrect symbols.


The Symbol Search subtest displays one or two symbols (depending on the age of the student) on the left hand side of the page. The student then must determine whether that symbol appears in a series of symbols displayed on the right side of the page. If the symbol appears, the student circles it. If not, the student checks the “No” box. The student has two minutes to complete as many items as possible. The student is then awarded one point for each correct answer but loses a point for each incorrect answer.


Once the two subtests are completed and scored, the score is then converted to a standard score that can be interpreted. The Processing Speed index score can be interpreted using the following scale:

• 130 or above: Very Superior
• 120-129: Superior
• 110-119: High Average
• 90-109: Average
• 80-89: Low Average
• 70-79: Borderline
• Below 70: Extremely Low

IQ Part 5: Processing Speed | EdPsyched

Welcome to the final installment of my deep dive into the IQ. We have already looked at the first four components: Verbal Comprehension, Visual Spatial, Fluid Reasoning and Working Memory. Today’s post will examine Processing Speed. As a reminder, I’ve been using the WISC-V for the basis of...

edpsyched.com

With our introduction to the PSI, let's begin:

After controlling for full scale IQ, the present results show that processing speed index standard scores were on average 12 points lower in the group with ASD compared to the group with typical development. There were, however, no significant group differences in standard score age-related changes within this age range. For subtest raw scores, the group with ASD demonstrated robustly slower processing speeds in the adult versions of the IQ test (i.e., WAIS-III) but not in the child versions (WISC-III), even though age-related changes were similar in both the ASD and typically developing groups. This pattern of results may reflect difficulties that become increasingly evident in ASD on more complex measures of processing speed. Finally, DTI measures of whole-brain white matter microstructure suggested that fractional anisotropy (but not mean diffusivity, radial diffusivity, or axial diffusivity) made significant but small-sized contributions to processing speed standard scores across our entire sample. Taken together, the present findings suggest that robust decreases in processing speed may be present in ASD, more pronounced in adulthood, and partially attributable to white matter microstructural integrity.

Longitudinal processing speed impairments in males with autism and the effects of white matter microstructure - PubMed

The present study used an accelerated longitudinal design to examine group differences and age-related changes in processing speed in 81 individuals with autism spectrum disorder (ASD) compared to 56 age-matched individuals with typical development (ages 6-39 years). Processing speed was...

pubmed.ncbi.nlm.nih.gov

Individuals with disorders that include psychotic symptoms (i.e. psychotic disorders) experience broad cognitive impairments in the chronic state, indicating a dimension of abnormality associated with the experience of psychosis. These impairments negatively impact functional outcome, contributing to the disabling nature of schizophrenia, bipolar disorder, and psychotic depression. The robust and reliable nature of cognitive deficits has led researchers to explore the timing and profile of impairments, as this may elucidate different neurodevelopmental patterns in individuals who experience psychosis. Here, we review the literature on cognitive deficits across the life span of individuals with psychotic disorder and psychotic-like experiences, highlighting the dimensional nature of both psychosis and cognitive ability. We identify premorbid generalized cognitive impairment in schizophrenia that worsens throughout development, and stabilizes by the first-episode of psychosis, suggesting a neurodevelopmental course.

Cognitive Deficits in Psychotic Disorders: A Lifespan Perspective - PubMed

Individuals with disorders that include psychotic symptoms (i.e. psychotic disorders) experience broad cognitive impairments in the chronic state, indicating a dimension of abnormality associated with the experience of psychosis. These impairments negatively impact functional outcome...

pubmed.ncbi.nlm.nih.gov

ASD and SSD affect cognition and processing speed, as indicated above.

Below is an example of my own genetic results:

The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability​

Genetic variants in and around the transcription factor 4 (TCF4) gene are associated with range of disorders that are frequently associated with cognitive dysfunction.1–3 The most recent schizophrenia GWAS reported three independent single nucleotide polymorphisms (SNPs) in TCF4 that surpassed the threshold for genome wide significance.4 Intriguingly, rare TCF4 single nucleotide variants (SNVs) have also been described in schizophrenia patients, although their impact on the function of the protein has not been established.5,6 In addition to the genetic studies in schizophrenia, TCF4 variants are associated with early information processing and cognitive markers, some of which are schizophrenia endophenotypes.7–10 Damaging TCF4 mutations have also been described in large-scale genotyping studies in patients with ID, neurodevelopmental disorders, and most recently ASD.11–15 Haploinsufficiency of TCF4 causes Pitt–Hopkins syndrome (PTHS); a rare form intellectual disability (ID) associated with characteristic facial features, autonomic dysfunction, and behavioral traits that resemble autism spectrum disorder (ASD).16–19 Collectively, these studies implicate TCF4 in a range of neurodevelopmental disorders.

CF4 is a member of the basic helix-loop-helix (bHLH) family of proteins.20–22 For the purposes of disambiguation, it should be noted that TCF4 (Gene ID: 6925) described herein should not be confused with T-cell factor 4 (Gene ID: 6934, official gene symbol, TCF7L2) since they can share the same acronym. TCF4 and its paralogues, collectively known as E-proteins, interact with other bHLH proteins to regulate DNA binding specificity and transcriptional activity at promoters and enhancers that contain E-boxes (5′-CANNTG).2,20,23 The human TCF4 gene encodes multiple protein isoforms of which only the major isoforms TCF4-A and TCF4-B have been characterized in detail.24 In neurons, TCF4 regulates the intrinsic excitability of pyramidal cells of the prefrontal cortex and has been shown to attenuate neurite branching.25,26 Furthermore, haploinsufficiency of Tcf4 in mice affects gene expression and DNA methylation in the brain, leading to enhanced long-term potentiation, learning and memory deficits, and autistic-like behavior.22,25,26 By contrast, mice over-expressing Tcf4 in the brain display deficits in sensorimotor gating, fear conditioning, and circadian processes as well as impairments in attentional and behavioral anticipation.7,27

The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability

AbstractBackground. Common genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizoph

academic.oup.com

 

[Intellau_Celistic]

Hello. Today we look at the CSF2RA Schizophrenia gene.

As always, I provide a sample of my own genetic results:

(It is X-linked)

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia​

​

Schizophrenia is a strongly heritable disorder, and identification of potential candidate genes has accelerated in recent years. Genomewide scans have identified multiple large linkage regions across the genome, with fine-mapping studies and other investigations of biologically plausible targets demonstrating several promising candidate genes of modest effect. The recent introduction of technological platforms for whole-genome association (WGA) studies can provide an opportunity to rapidly identify novel targets, although no WGA studies have been reported in the psychiatric literature to date. We report results of a case-control WGA study in schizophrenia, examining approximately 500 000 markers, which revealed a strong effect (P=3.7 x 10(-7)) of a novel locus (rs4129148) near the CSF2RA (colony stimulating factor, receptor 2 alpha) gene in the pseudoautosomal region. Sequencing of CSF2RA and its neighbor, IL3RA (interleukin 3 receptor alpha) in an independent case-control cohort revealed both common intronic haplotypes and several novel, rare missense variants associated with schizophrenia. The presence of cytokine receptor abnormalities in schizophrenia may help explain prior epidemiologic data relating the risk for this illness to altered rates of autoimmune disorders, prenatal infection and familial leukemia.

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia - PubMed

Schizophrenia is a strongly heritable disorder, and identification of potential candidate genes has accelerated in recent years. Genomewide scans have identified multiple large linkage regions across the genome, with fine-mapping studies and other investigations of biologically plausible targets...

pubmed.ncbi.nlm.nih.gov

Variations in that gene are therefore believed to cause SSD. Simple...

 

[Intellau_Celistic]

So does this mean you're schizophrenic?

No. I am autistic. I'll post others in a moment...

 

[Intellau_Celistic]

Now we look at the MET gene.

Sample:

Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder​

Pamela B Jackson 1 , Luigi Boccuto, Cindy Skinner, Julianne S Collins, Giovanni Neri, Fiorella Gurrieri, Charles E Schwartz

Affiliations

• PMID: 19681062
• DOI: 10.1002/aur.87

Abstract​

Previous studies in three independent cohorts have shown that the rs1858830 C allele variant in the promoter region of the MET gene on chromosome 7q31 is associated with autism. Another study has found correlations between other alterations in the MET gene and autism in two unrelated cohorts. This study screened two cohorts, an Autistic Disorder cohort from South Carolina and a Pervasive Developmental Disorder (PDD) cohort from Italy, for the presence of the C allele variant in rs1858830. A significant increase in the C allele variant frequency was found in the South Carolina Autistic Disorder patients as compared to South Carolina Controls (chi(2)=5.8, df=1, P=0.02). In the South Carolina cohort, a significant association with Autistic Disorder was found when comparing the CC and CG genotypes to the GG genotype (odds ratio (OR)=1.64; 95% confidence interval (CI)=1.12-2.40; chi(2)=6.5, df=1, P=0.01) in cases and controls. In the Italian cohort, no significant association with PDD was found when comparing the CC or CG genotype to the GG genotype (OR=1.20; 95% CI=0.56-2.56; chi(2)=0.2, df=1, P=0.64). This study is the third independent study to find the rs1858830 C variant in the MET gene promoter to be associated with autism.

Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder - PubMed

Previous studies in three independent cohorts have shown that the rs1858830 C allele variant in the promoter region of the MET gene on chromosome 7q31 is associated with autism. Another study has found correlations between other alterations in the MET gene and autism in two unrelated cohorts...

pubmed.ncbi.nlm.nih.gov

 

[Intellau_Celistic]

Next is the infamous CNTNAP2 gene, another ASD gene.

After a bit of distraction, here is my sample...:

The association of CNTNAP2 rs7794745 gene polymorphism and autism in Iranian population​

Sahar Zare 1 , Farhad Mashayekhi 2 , Elham Bidabadi 3

Affiliations

• PMID: 28284582
• DOI: 10.1016/j.jocn.2017.01.008

Abstract​

Autism is a heterogeneous and multifactorial disease that results from the interaction between genetic vulnerability and environmental factors. Several studies showed that many of genes that play role in autism are component of signaling networks that regulate growth and synaptic plasticity, play an important role in the etiology of autism. Contactin associated-like 2 (CNTNAP2) gene is a member of the superfamily of synaptic adhesion proteins and encodes a scaffold protein called CASPR2 that is involved in the interaction of neuron-glia and clusters K+ channels in myelinated axons. CNTNAP2 is highly expressed during the nervous system development. In this study the association of rs7794745 CNTNAP2 gene polymorphism and autism was investigated. Two hundred patients with autism and 260 healthy individuals were included in this study. Genomic DNA was extracted from peripheral blood cells. Genotypes were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Statistical analysis was performed using the software MedCalc (12.1). The genotype frequencies of AA, AT, TT were 35.3%, 50.7% and 13.8% in controls and these values were 32% and 68% and 0% in patients with autism, respectively (P=0.0001) (OR=0.01, 95% CI 0.001-0.32). The frequency of A and T alleles were 66%, 34% in patients and 60%, 40% in controls, respectively (P=0.11). The results of this study showed that there is a significant association between rs7794745 CNTNAP2 gene polymorphism and autism in the studied population. However, to obtain a definitive conclusion larger studies with more patients and controls are needed to confirm the results.

The association of CNTNAP2 rs7794745 gene polymorphism and autism in Iranian population - PubMed

Autism is a heterogeneous and multifactorial disease that results from the interaction between genetic vulnerability and environmental factors. Several studies showed that many of genes that play role in autism are component of signaling networks that regulate growth and synaptic plasticity...

pubmed.ncbi.nlm.nih.gov

 

[Intellau_Celistic]

Our last ASD gene(From my results) is shown here. This one is commonly found among Africans.

Systemizing is genetically correlated with autism and is genetically distinct from social autistic traits​

Abstract​

The hypersystemizing theory of autism suggests that autistic individuals, on average, have superior attention to detail, and a stronger drive to systemize. Systemizing involves identifying input-operation-output relationships. Here, we report the results of genome-wide association studies (GWAS) of systemizing measured using the Systemizing Quotient - Revised in n = 51,564 individuals. We identify three genome-wide significant loci: Two of these were significant in the non-stratified GWAS: rs4146336 on chromosome 3 (P = 2.58×10−8) and rs1559586 on chromosome 18 (P = 4.78×10−8). In addition, we also identified a significant locus in the males-only GWAS (rs8005092 on chromosome 14, P = 3.74×10−8). We find that 12%± 1.2 of the variance in systemizing is captured by SNPs (P=1.2×10−20). We identify a positive genetic correlation between autism and systemizing (rg = 0.26±0.06; P = 3.35×10−5), which is independent of genetic contribution to educational attainment. We further demonstrate that genetic risk for autism from systemizing is genetically distinct from genetic risk emerging from social autistic traits, suggesting distinct shared genetics between autism and social and non-social traits. Our results highlight the importance of considering both social and non-social autistic traits in elucidating the genetic architecture of autism.

Systemizing is genetically correlated with autism and is genetically distinct from social autistic traits

The hypersystemizing theory of autism suggests that autistic individuals, on average, have superior attention to detail, and a stronger drive to systemize. Systemizing involves identifying input-operation-output relationships. Here, we report the results of genome-wide association studies (GWAS)...

www.biorxiv.org

 

[bigantennaemay1]

So in other words, I'm a birth defect because I have autism.

 

[Asgard]

Brutal neuroatypicalpill

 

[iceandblood]

So in other words, I'm a birth defect because I have autism.

 

[12 Years a Rotter]

tldr big science words me no read aha xd

 

[Deleted member 38680]

I'm on the schizophrenia spectrum (shizoaffective) and I feel mentally impaired. Life has been hell ever since my mind started getting wacky.

 

[Deleted member 41516]

I'm on the schizophrenia spectrum (shizoaffective) and I feel mentally impaired. Life has been hell ever since my mind started getting wacky.

How old were you when your mind started getting wacky

 

[racoon4]

 

[Deleted member 38680]

How old were you when your mind started getting wacky

16

 

[Stonersperg]

It's fucking hell having both

 

[Intellau_Celistic]

@Proton

 

[Intellau_Celistic]

Interesting, i was misdiagnosed with autism when i was younger, it turned out to be schizophrenia though. Ive been psychosis before.

I was diagnosed with visual psychosis, but it is actually Palinopsia from ASD.

 

[NoLooksNoLife]

I probably have both without knowing

 

[Intellau_Celistic]

I probably have both without knowing

Rs9960767 gave me Palinopsia, though I consider myself to have only ASD.

 

[Intellau_Celistic]

 

[Intellau_Celistic]

Association of Dopamine Beta-Hydroxylase Polymorphisms with Alzheimer’s Disease, Parkinson’s Disease and Schizophrenia: Evidence Based on Currently Available Loci

Background/Aims: The neuropathies Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SCZ) have different pathological mechanisms but share some common neurodegenerative features, such as gradual loss of neuronal structure and function. Dopamine beta-hydroxylase (DBH), a gene...

www.karger.com

In summary, the DBH rs2283123 and rs2007153 polymorphisms might influence SCZ risk, but the DBH 5’-Ins/Del, rs1108580, rs1611115, and rs4531 polymorphisms and the combination of all 13 DBH loci were not associated with the risk of SCZ development.

 

[Asgard]

Recalling my latest experiences, my processing speed seems to be sub-par when compared to other peers.

Mensa.dk situated my IQ within 115-116, always. Those Raven metric tests tend to be deflated/inflated, according to some Reddit threads on this matter.

For instance, I took a WAIS-IV in my teenage years (administred by social security psychiatrist). My results were undisclosed, unfortunately.


I'd say my real IQ is well below 100.

 

[Asgard]

* Fixed grammar.

 

[Diddy29]

This makes a lot of sense. My brother has autism and I have schizophrenia .

 

[brain edinberg]

This makes a lot of sense. My brother has autism and I have schizophrenia .

 

[To koniec]

It's fucking hell having both

i have both...

@Transcended Trucel
@Mecoja
@Copexodius Maximus
@Intellau_Celistic

 

[Old Ironsides]

It won’t start.



over

 

[Med Amine]

i don't know what all that shit mean but i am probably totally sane person or maybe not, i really don't care since i can talk with people normally without any problem
good luck bro

 

[Intellau_Celistic]

i don't know what all that shit mean but i am probably totally sane person

It won’t start.

 

[Intellau_Celistic]

Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism​

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of a limited number of common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) on 6222 case-pseudocontrol pairs from the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD. We identified one novel GWS locus from the SPARK GWAS and four significant loci, including an additional novel locus from meta-analysis with a previous GWAS. We replicated the previous observation of significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. We further employed a massively parallel reporter assay (MPRA) and identified a putative causal variant at the novel locus from SPARK GWAS with strong impacts on gene regulation (rs7001340). Expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and prenatal brains. In conclusion, by integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism - Translational Psychiatry

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of a limited number of common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants...

www.nature.com

(Requested)

 

[KILLMANKIND]

Being schizophrenic is fucking hell. I should be thankful I'm not autistic aswell. Life's already shitty enough with my schizo ass.

 

[Intellau_Celistic]

 

[Intellau_Celistic]

In conclusion, by integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

 

[Intellau_Celistic]

Donald Triplett, first person to be diagnosed with autism dies at 89

Donald Triplett, the first person ever diagnosed with autism, has passed away at the age of 89 - he had an uncanny knack for memorization.

www.dailymail.co.uk

 

[Intellau_Celistic]

Talent in autism comes in many forms, but a common characteristic is that the individual becomes an expert in recognizing repeating patterns in stimuli. We call this systemizing, defined as the drive to analyse or construct systems. These might be any kind of system. What defines a system is that it follows rules, and when we systemize we are trying to identify the rules that govern the system, in order to predict how that system will behave (Baron-Cohen 2006). These are some of the major kinds of system.

...

Systemizing is genetically correlated with autism and is genetically distinct from social autistic traits​

These initial clinical observations have been quantified using different measures. For example, on a self-report measure of systemizing (the Systemizing Quotient – Revised, or the SQ-R)4, autistic adults, on average, score significantly higher than non-autistic individuals4,5. The same pattern of results is seen in autistic children, using the parent-report version of the SQ6. Systemizing is also highly correlated with aptitude in science, technology, engineering, and mathematics (STEM)7. Fathers and grandfathers of children with autism are significantly overrepresented in the field of engineering8. The same is true of mothers9. This is in line with higher rates of autism in geographical regions that have higher rates of people working in fields such as information technology, like Eindhoven in the Netherlands10. Further, autistic individuals are more likely to enrol in STEM majors (34.31%) compared to the general population (22.8%) and other learning disabilities (18.6%)11. STEM professionals also score significantly higher on measures of autistic traits (mean = 21.92, SD = 8.92) compared non-STEM professionals (mean = 18.92, SD = 8.48)12. Finally, unpublished work from Sweden suggests that high technical IQ in fathers increases risk for autism in children. A few studies have also investigated systemizing in other psychiatric traits and conditions, including schizotypy13 and anorexia nervosa14.

Systemizing is genetically correlated with autism and is genetically distinct from social autistic traits

The hypersystemizing theory of autism suggests that autistic individuals, on average, have superior attention to detail, and a stronger drive to systemize. Systemizing involves identifying input-operation-output relationships. Here, we report the results of genome-wide association studies (GWAS)...

www.biorxiv.org

 

[Intellau_Celistic]

 

[Intellau_Celistic]

 

[Intellau_Celistic]

 

[ecwsan13]

What an informative post.

 

[Intellau_Celistic]

...

Here, we report the results of genome-wide association studies (GWAS) of systemizing measured using the Systemizing Quotient - Revised in n = 51,564 individuals. We identify three genome-wide significant loci: Two of these were significant in the non-stratified GWAS: rs4146336 on chromosome 3 (P = 2.58×10−8) and rs1559586 on chromosome 18 (P = 4.78×10−8). In addition, we also identified a significant locus in the males-only GWAS (rs8005092 on chromosome 14, P = 3.74×10−8). We find that 12%± 1.2 of the variance in systemizing is captured by SNPs (P=1.2×10−20). We identify a positive genetic correlation between autism and systemizing (rg = 0.26±0.06; P = 3.35×10−5), which is independent of genetic contribution to educational attainment. We further demonstrate that genetic risk for autism from systemizing is genetically distinct from genetic risk emerging from social autistic traits, suggesting distinct shared genetics between autism and social and non-social traits. Our results highlight the importance of considering both social and non-social autistic traits in elucidating the genetic architecture of autism.

 

[Intellau_Celistic]

(Requested)

\

 

[Intellau_Celistic]

Identification of common genetic risk variants for autism spectrum disorder​

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture, we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454898/

European	Sub	9654	A=0.9724	G=0.0276, T=0.0000
African	Sub	2808	A=0.9352	G=0.0648, T=0.0000
African Others	Sub	106	A=0.906	G=0.094, T=0.000
African American	Sub	2702	A=0.9363	G=0.0637, T=0.0000
Asian	Sub	112	A=1.000	G=0.000, T=0.000
East Asian	Sub	86	A=1.00	G=0.00, T=0.00
Other Asian	Sub	26	A=1.00	G=0.00, T=0.00
Latin American 1	Sub	146	A=0.952	G=0.048, T=0.000
Latin American 2	Sub	610	A=0.975	G=0.025, T=0.000

 

[Intellau_Celistic]

...

I'll begin in a moment.

 

[Intellau_Celistic]

• This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF4

 

[Intellau_Celistic]

In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressing TCF4 in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility gene TCF4 (rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n = 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total sample n = 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of the TCF4 gene (meta-analysis across both samples: p = 0.00002), whereas startle reactivity and habituation were unaffected by TCF4 genotype. Sensorimotor gating is modulated by TCF4 genotype, indicating an influential role of TCF4 gene variations in the development of early information-processing deficits in schizophrenia.

The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers - PubMed

In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressing TCF4 in the brain display a reduction of sensorimotor gating measured by prepulse...

pubmed.ncbi.nlm.nih.gov

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667105/

It remains unclear whether the diversity of disorders exhibiting deficient PPI bespeaks diagnostic overlaps or comorbidities. Given the recent focus on treatments for cognitive deficits of schizophrenia independently of treating psychosis, the relationship of PPI deficits to cognitive deficits becomes of interest. Although PPI cannot be considered to be a cognitive process per se, abnormalities in pre-attentive information processing may be predictive of or lead to complex cognitive deficits. Animal models of PPI deficits produced by dopamine agonists reliably predict existing antipsychotics. Nevertheless, since neither PPI nor cognitive deficits in schizophrenia are ameliorated by standard antipsychotics, current research is exploring the predictive value of non-dopaminergic PPI models in identifying treatments for gating disturbances independently of their relevance to specific disorders. Both PPI and cognitive deficits in schizophrenia patients are not reversed by first generation antipsychotics but may be attenuated by clozapine. Similarly, effects of glutamate antagonists on symptoms in patients and PPI in animals appear to be reduced by clozapine. Hence, treatment-induced reversals of deficits in PPI produced by glutamate antagonists may provide animal, and human, models to aid in the discovery of treatments of cognitive deficits in patients already treated with existing antipsychotics.

 

[Intellau_Celistic]

...

Attention deficits and inappropriate regulation of sensory signal processing are hallmarks of many neuropsychiatric conditions, including attention deficit hyperactivity, for which methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed therapeutic treatments. Despite their widespread use and known mechanism of blocking reuptake of catecholamine transmitters in the brain, the resultant actions on individual neuron and neural circuit function that lead to therapeutic efficacy are poorly understood. Given the ability of MPH and ATX to improve cognitive performance in humans and rodent assays of attention, we were interested in their influence on early sensory processing in the dorsal lateral geniculate nucleus (dLGN), the primary thalamic relay for visual information from the retina to the visual cortex. In male rats, dLGN neuronal responses to light stimuli were altered in multiple ways after doses of MPH or ATX observed to enhance performance in visually guided assays of attention (MPH = 2 mg/kg; ATX = 0.5 mg/kg). Latencies to response onset and to the peak of the primary response were decreased, while the peak intensity and area of the primary response were increased. In addition, some cells that were unresponsive to light stimuli prior to drug treatment displayed a "gating effect," wherein prominent responses to light stimuli were evident after drug administration. Our results begin to reveal unique effects of MPH and ATX in enhancing sensory signal transmission through visual circuitry, and may yield new insights for understanding the pathophysiology of certain cognitive disorders and inform development of improved therapeutic treatments for these conditions.

Methylphenidate and atomoxetine enhance sensory-evoked neuronal activity in the visual thalamus of male rats - PubMed

Attention deficits and inappropriate regulation of sensory signal processing are hallmarks of many neuropsychiatric conditions, including attention deficit hyperactivity, for which methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed therapeutic treatments. Despite their...

pubmed.ncbi.nlm.nih.gov

Conclusion: Heterogeneity of ADHD is confirmed with a wide range of baseline PPI. The improvement of reduced baseline PPI through MPH suggests impaired sensorimotor gating in this subgroup.

Methylphenidate and atomoxetine enhance sensory-evoked neuronal activity in the visual thalamus of male rats - PubMed

Attention deficits and inappropriate regulation of sensory signal processing are hallmarks of many neuropsychiatric conditions, including attention deficit hyperactivity, for which methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed therapeutic treatments. Despite their...

pubmed.ncbi.nlm.nih.gov

 

[Intellau_Celistic]

Effects of methylphenidate on sensory and sensorimotor gating of initially psychostimulant-naïve adult ADHD patients - PubMed

Deficient information processing in ADHD theoretically results in sensory overload, which in turn may underlie its symptoms. If this sensory overload is caused by deficient filtering of environmental stimuli, then one would expect finding deficits in P50 gating and prepulse inhibition of the...

pubmed.ncbi.nlm.nih.gov

The absence of PPI and P50 suppression deficits in our patients in the psychostimulant-naïve state indicates no gating deficits. In turn, this suggests that the difficulties to inhibit distraction of attention by irrelevant stimuli that many patients with (adult) ADHD report, have a different origin than the theoretical causes of sensory overload frequently reported in studies on patients with schizophrenia.

 

[ldargoblin]

I read every single word

 

[Intellau_Celistic]

Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Associates with the BLOC-2 complex to facilitate the transport of TYRP1 independent of AP-3 function. Plays a role in synaptic vesicle trafficking and in neurotransmitter release. Plays a role in the regulation of cell surface exposure of DRD2. May play a role in actin cytoskeleton reorganization and neurite outgrowth. May modulate MAPK8 phosphorylation. Appears to promote neuronal transmission and viability through regulating the expression of SNAP25 and SYN1, modulating PI3-kinase-Akt signaling and influencing glutamatergic release. Regulates the expression of SYN1 through binding to its promoter. Modulates prefrontal cortical activity via the dopamine/D2 pathway. (DTBP1_HUMAN,Q96EV8 )

Background: The human dystrobrevin binding protein 1 (DTNBP1) gene has been linked to risk for schizophrenia. Recent studies indicate that several single nucleotide polymorphisms (SNPs) in the DTNBP1 gene may also influence general cognitive ability in both schizophrenic patients and healthy control subjects. We examined the relationship between DTNBP1 SNPs and general cognitive ability in nonpsychiatric healthy samples via meta-analysis.

Results: Pooled effect sizes from two of the nine SNPs (rs1018381 and rs2619522) were -.123 and -.083, ps < .01, respectively, suggesting that the minor allele carriers of these SNPs had lower cognitive ability scores than the major allele homozygotes. Results remained significant after examining heterogeneity among samples and potential publication biases. Other SNPs did not show significant effects on general cognitive ability.


Conclusions: Genetic variation in DTNBP1 modestly influences general cognitive ability. Further studies are needed to elucidate the biological mechanisms that may account for this relationship.

Meta-analysis of genetic variation in DTNBP1 and general cognitive ability - PubMed

Genetic variation in DTNBP1 modestly influences general cognitive ability. Further studies are needed to elucidate the biological mechanisms that may account for this relationship.

pubmed.ncbi.nlm.nih.gov

 

[der_komische]

sex