Patient-Driven Findings of Genetic Associations for PANS and PANDAS

Background: There are presently very few genetic studies for PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome) or PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). More work in genetic associations for PANS and PANDAS (P/P) is needed to increase understanding of these debilitating childhood disorders that have a range of presentations.Objective: This work represents a novel approach that aims to determine genetic associations between P/P and other diseases, disorders and traits (hereafter referred to as phenotypes).Methods: Consumer genetic data (23andMe, AncestryDNA) for 155 patients with P/P were obtained from consenting parents over a period from 2018 to 2020. An analysis plan for this work was registered at Open Science Framework, additional genotypes imputed using Impute.me, and polygenic risk scores for 1,702 phenotypes calculated for each of the 155 P/P patients.Results: One-sample t-tests performed across the 155 individual risk scores revealed that P/P is statistically significantly associated with 21 different groups of Single Nucleotide Polymorphisms (SNPs) that are in turn associated with 21 phenotypes. Some of the 21 phenotypes (see Table 3) are previously known to be related to or associated with P/P: a group of SNPs associated with Tourette’s Syndrome, and another group associated with Autism Spectrum Disorder or Schizophrenia, and a third associated with “feeling nervous” yielded t-tests with p values of 1.2x10-5, 1.2x10-11 and 1.0x10-5 respectively for association with the P/P data. This validated our analysis methodology. Our analysis also revealed novel genetic associations such as between P/P and plasma anti-thyroglobulin levels (p=1.3x10-7), between P/P and triglycerides (p=5.6x10-6), and between P/P and Lewy body disease (p=7.8x10-6), inviting further investigation into the underlying etiology of P/P.Conclusion: P/P is associated with many phenotypes not previously recognized as being connected to P/P. Further work on these connections can lead to better understanding of P/P.

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Using synthetic datasets to bridge the gap between the promise and reality of basing health-related decisions on common single nucleotide polymorphisms

F1000Research ◽

10.12688/f1000research.21797.1 ◽

2019 ◽

Vol 8 ◽

pp. 2147

Author(s):

Thomas R. Wood ◽

Nathan Owens

Keyword(s):

Single Nucleotide Polymorphisms ◽

Disease Risk ◽

Methylation Status ◽

Fasting Blood Glucose ◽

Risk Scores ◽

Individual Risk ◽

Common Snps ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Synthetic Datasets

Background: While the academic genetic literature has clearly shown that common genetic single nucleotide polymorphisms (SNPs), and even large polygenic SNP risk scores, cannot reliably be used to determine risk of disease or to personalize interventions, a significant industry of companies providing SNP-based recommendations still exists. Healthcare practitioners must therefore be able to navigate between the promise and reality of these tools, including being able to interpret the literature that is associated with a given risk or suggested intervention. One significant hurdle to this process is the fact that most population studies of common SNPs only provide average (+/- error) phenotypic or risk descriptions for a given genotype, which hides the true heterogeneity of the population and reduces the ability of an individual to determine how they themselves or their patients might truly be affected. Methods: We generated synthetic datasets generated from descriptive phenotypic data published on common SNPs associated with obesity, elevated fasting blood glucose, and methylation status. Using simple statistical theory and full graphical representation of the generated data, we developed a method by which anybody can better understand phenotypic heterogeneity in a population, as well as the degree to which common SNPs truly drive disease risk. Results: Individual risk SNPs had a <10% likelihood of effecting the associated phenotype (bodyweight, fasting glucose, or homocysteine levels). Example polygenic risk scores including the SNPs most associated with obesity and type 2 diabetes only explained 2% and 5% of the final phenotype, respectively. Conclusions: The data suggest that most disease risk is dominated by the effect of the modern environment, providing further evidence to support the pursuit of lifestyle-based interventions that are likely to be beneficial regardless of genetics.

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Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

10.1101/2021.01.08.20249006 ◽

2021 ◽

Author(s):

Aditya Ambati ◽

Ryan Hillary ◽

Smaranda Leu-Semenescu ◽

Hanna M. Ollila ◽

Ling Lin ◽

...

Keyword(s):

Bipolar Disorder ◽

Genome Wide Association Study ◽

Lithium Treatment ◽

Gene Region ◽

Risk Scores ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Genome Wide ◽

Increased Risk

AbstractKleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6×10−9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3’ region of TRANK1 gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reduced TRANK1 rs71947865 association. While theTRANK1 rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p<2.0×10−22 at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.Significance StatementGenetic markers in TRANK1 gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in the TRANK1 gene region may predispose to KLS when patients have had a difficult birth, suggesting that TRANK1 gene region modulate newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.

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Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers

Genes ◽

10.3390/genes12050686 ◽

2021 ◽

Vol 12 (5) ◽

pp. 686

Author(s):

Alireza Nazarian ◽

Alexander M. Kulminski

Keyword(s):

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Significance Level ◽

Association Analyses ◽

Complex Disorders ◽

Specific Effects ◽

Genome Wide ◽

Genetic Mechanisms ◽

Sex Disparities ◽

Almost All

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.

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Investigation of gene–environment interactions in relation to tic severity

Journal of Neural Transmission ◽

10.1007/s00702-021-02396-y ◽

2021 ◽

Author(s):

Mohamed Abdulkadir ◽

Dongmei Yu ◽

Lisa Osiecki ◽

Robert A. King ◽

Thomas V. Fernandez ◽

...

Keyword(s):

Tourette Syndrome ◽

Association Studies ◽

Autism Spectrum ◽

Environment Interaction ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Linear Regression Models ◽

Compulsive Disorder ◽

Gene Environment ◽

Tic Severity

AbstractTourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.

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In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Toxics ◽

10.3390/toxics9050097 ◽

2021 ◽

Vol 9 (5) ◽

pp. 97

Author(s):

Tristan Furnary ◽

Rolando Garcia-Milian ◽

Zeyan Liew ◽

Shannon Whirledge ◽

Vasilis Vasiliou

Keyword(s):

Autism Spectrum Disorder ◽

Prenatal Exposure ◽

Pesticide Exposure ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Biomedical Literature ◽

Spectrum Disorder ◽

Biological Processes ◽

Genetic Associations ◽

Increased Risk

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

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The patterns of family genetic risk scores for eleven major psychiatric and substance use disorders in a Swedish national sample

Translational Psychiatry ◽

10.1038/s41398-021-01454-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kenneth S. Kendler ◽

Henrik Ohlsson ◽

Jan Sundquist ◽

Kristina Sundquist

Keyword(s):

Genetic Risk ◽

Molecular Genetic ◽

National Sample ◽

Autism Spectrum ◽

Risk Scores ◽

Pedigree Data ◽

Obsessive Compulsive ◽

Swedish Population ◽

Compulsive Disorder ◽

Genetic Risk Scores

AbstractTo clarify the structure of genetic risks for 11 major psychiatric disorders, we calculated, from morbidity risks for disorders in 1st–5th degree relatives controlling for cohabitation effects, in the Swedish population born between 1932 and 1995 (n = 5,830,014), the family genetic risk scores (FGRS) for major depression (MD), anxiety disorders (AD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), bulimia (BUL), anorexia nervosa (AN), alcohol use disorder (AUD), drug use disorder (DUD), ADHD, and autism-spectrum disorder (ASD). For all affected individuals, we calculated their mean standardized FGRS for each disorder. The patterns of FGRS were quite similar for MD and AD, and for AUD and DUD, but substantially less similar for BUL and AN, BD and SZ, and ADHD and ASD. While OCD had high levels of FGRS for MD and AD, the overall FGRS profile differed considerably from MD and AD. ADHD FGRS scores were substantially elevated in AUD and DUD. FGRS scores for BD, OCD, AN, ASD, ADHD, and especially SZ were relatively disorder-specific while genetic risk for MD and AD had more generalized effects. The levels of FGRS for BMI, coronary artery disease, and educational attainment across our disorders replicated prior associations found using molecular genetic methods. All diagnostic categories examined had elevated FGRS for many disorders producing, for each condition, an informative FGRS profile. Using a novel method which approximates, from pedigree data, aggregate genetic risk, we have replicated and extended prior insights into the structure of genetic risk factors for key psychiatric illnesses.

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Effects of polygenic risk for major mental disorders and cross-disorder on cortical complexity

Psychological Medicine ◽

10.1017/s0033291721001082 ◽

2021 ◽

pp. 1-12

Author(s):

Simon Schmitt ◽

Tina Meller ◽

Frederike Stein ◽

Katharina Brosch ◽

Kai Ringwald ◽

...

Keyword(s):

Bipolar Disorder ◽

Mental Disorders ◽

Cortical Thickness ◽

Genetic Risk ◽

Right Hemisphere ◽

Autism Spectrum ◽

Risk Scores ◽

Grey Matter Volume ◽

Polygenic Risk ◽

Risk For Depression

Abstract Background MRI-derived cortical folding measures are an indicator of largely genetically driven early developmental processes. However, the effects of genetic risk for major mental disorders on early brain development are not well understood. Methods We extracted cortical complexity values from structural MRI data of 580 healthy participants using the CAT12 toolbox. Polygenic risk scores (PRS) for schizophrenia, bipolar disorder, major depression, and cross-disorder (incorporating cumulative genetic risk for depression, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder) were computed and used in separate general linear models with cortical complexity as the regressand. In brain regions that showed a significant association between polygenic risk for mental disorders and cortical complexity, volume of interest (VOI)/region of interest (ROI) analyses were conducted to investigate additional changes in their volume and cortical thickness. Results The PRS for depression was associated with cortical complexity in the right orbitofrontal cortex (right hemisphere: p = 0.006). A subsequent VOI/ROI analysis showed no association between polygenic risk for depression and either grey matter volume or cortical thickness. We found no associations between cortical complexity and polygenic risk for either schizophrenia, bipolar disorder or psychiatric cross-disorder when correcting for multiple testing. Conclusions Changes in cortical complexity associated with polygenic risk for depression might facilitate well-established volume changes in orbitofrontal cortices in depression. Despite the absence of psychopathology, changed cortical complexity that parallels polygenic risk for depression might also change reward systems, which are also structurally affected in patients with depressive syndrome.

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Influence of single nucleotide polymorphisms on thrombin generation in factor V Leiden heterozygotes

Thrombosis and Haemostasis ◽

10.1160/th13-05-0360 ◽

2014 ◽

Vol 111 (03) ◽

pp. 438-446 ◽

Cited By ~ 8

Author(s):

Olivier Segers ◽

Paolo Simioni ◽

Daniela Tormene ◽

Elisabetta Castoldi

Keyword(s):

Thrombin Generation ◽

Factor V Leiden ◽

Individual Variability ◽

Intermediate Phenotype ◽

Individual Risk ◽

Factor V ◽

Nucleotide Polymorphisms ◽

Factor X ◽

Large Variability ◽

Fv Leiden

SummaryCarriership of the factor V (FV) Leiden mutation increases the risk of venous thromboembolism (VTE) ~4-fold, but the individual risk of each FV Leiden carrier depends on several co-inherited risk and protective factors. Under the hypothesis that thrombin generation might serve as an intermediate phenotype to identify genetic modulators of VTE risk, we enrolled 188 FV Leiden heterozygotes (11 with VTE) and determined the following parameters: thrombin generation in the absence and presence of activated protein C (APC); plasma levels of prothrombin, factor X, antithrombin, protein S and tissue factor pathway inhibitor; and the genotypes of 24 SNPs located in the genes encoding these coagulation factors and inhibitors. Multiple regression analysis was subsequently applied to identify the (genetic) determinants of thrombin generation. The endogenous thrombin potential (ETP) showed a striking inter-individual variability among different FV Leiden carriers and, especially when measured in the presence of APC, correlated with VTE risk. Several SNPs in the F2 (rs1799963, rs3136516), F10 (rs693335), SERPINC1 (rs2227589), PROS1 (Heerlen polymorphism) and TFPI (rs5940) genes significantly affected the ETPAPC and/or the ETP+APC in FV Leiden carriers. Most of these SNPs have shown an association with VTE risk in conventional epidemiological studies, suggesting that the genetic dissection of thrombin generation leads to the detection of clinically relevant SNPs. In conclusion, we have identified several SNPs that modulate thrombin generation in FV Leiden heterozygotes. These SNPs may help explain the large variability in VTE risk observed among different FV Leiden carriers.

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Non-expert ratings of infant and parent emotion: Concordance with expert coding and relevance to early autism risk

International Journal of Behavioral Development ◽

10.1177/0165025409350365 ◽

2009 ◽

Vol 34 (1) ◽

pp. 88-95 ◽

Cited By ~ 18

Author(s):

Jason K. Baker ◽

John D. Haltigan ◽

Ryan Brewster ◽

James Jaccard ◽

Daniel Messinger

Keyword(s):

Autism Spectrum ◽

Parent Ratings ◽

Face To Face ◽

Coding Systems ◽

Behavioral Coding ◽

Novel Approach ◽

The Face ◽

High Concordance ◽

Spectrum Disorders ◽

Expert Ratings

This study investigated a novel approach to obtaining data on parent and infant emotion during the Face-to-Face/Still-Face paradigm, and examined these data in light of previous findings regarding early autism risk. One-hundred and eighty eight non-expert students rated 38 parents and infant siblings of children who did (20) or did not (18) have autism spectrum disorders. Ratings averaged across 10 non-experts exhibited high concordance with expert facial-action codes for infant emotion, and 20 non-experts were required for reliable parent ratings. Findings replicated the well-established still-face effect and identified subtle risk associations consonant with results from previous investigations. The unique information offered by intuitive non-expert ratings is discussed as an alternative to complex and costly behavioral coding systems.

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Detecting Genetic Associations betweenATG5and Lupus Nephritis bytrans-eQTL

Journal of Immunology Research ◽

10.1155/2015/153132 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 8

Author(s):

Yue-miao Zhang ◽

Fa-juan Cheng ◽

Xu-jie Zhou ◽

Yuan-yuan Qi ◽

Ping Hou ◽

...

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Clinical Information ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Single Nucleotide ◽

Genetic Studies ◽

Genome Wide ◽

Custom Made ◽

Regulatory Effects

Objectives. Numerous loci were identified to perturb gene expression intrans. As elevatedATG5expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated withATG5expression in a Chinese population with lupus nephritis (LN).Methods. The online expression quantitative trait loci database was searched fortrans-expression single nucleotide polymorphisms (trans-eSNPs) ofATG5. Taggingtrans-eSNPs were genotyped by a custom-made genotyping chip in 280 patients and 199 controls. For positive findings, clinical information and bioinformation analyses were performed.Results. Fourtrans-eSNPs were observed to be associated with susceptibility to LN (P< 0.05), including ANKRD50 rs17008504, AGA rs2271100, PAK7 rs6056923, and TET2 rs1391441, while seven othertrans-eSNPs showed marginal significant associations (0.05 <P< 0.1). Correlations between thetrans-eSNPs andATG5expression and different expression levels ofATG5in SLE patients and controls were validated, and their regulatory effects were annotated. However, no significant associations were observed between different genotypes oftrans-eSNPs and severity or outcome of the patients.Conclusion. Using the new systemic genetics approach, we identified 10 loci associated with susceptibility to LN potentially, which may be complementary to future pathway based genetic studies.

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