General personality dimensions, impairment and treatment response in obsessive-compulsive disorder.

General personality dimensions are associated with clinical severity and treatment response in individuals with depression and many anxiety disorders, but little is known about these relationships in individuals with obsessive-compulsive disorder (OCD). Individuals in the current study included 705 adults with OCD who had participated in family and genetic studies of the disorder. Participants self-completed the Neuroticism, Extraversion, Openness Personality Inventory or Neuroticism, Extraversion, Openness Five-Factor Inventory-3. Relationships between personality scores, and subjective impairment and OCD treatment response, were evaluated. The odds of subjective impairment increased with (unit increase in) the neuroticism score (odds ratio, OR = 1.03; 95% CI = 1.01-1.04; p < 0.01) and decreased with extraversion scores (OR = 0.98; 95% CI = 0.96-0.99; p < 0.01). The odds of reporting a good response to serotonin/selective serotonin reuptake inhibitors (OR = 1.02; 95% CI = 1.01-1.04; p < 0.01) or cognitive behavioural therapy (OR = 1.03; 95% CI = 1.01-1.05; p < 0.01) increased with the extraversion score. The magnitude of these relationships did not change appreciably after adjusting for other clinical features related to one or more of the personality dimensions. The findings suggest that neuroticism and extraversion are associated with subjective impairment, and that extraversion is associated with self-reported treatment response, in individuals with OCD. © 2019 John Wiley & Sons, Ltd.

Immune-Related Comorbidities in Childhood-Onset Obsessive Compulsive Disorder: Lifetime Prevalence in the Obsessive Compulsive Disorder Collaborative Genetics Association Study.

Objective: To evaluate the lifetime prevalence of infectious, inflammatory, and autoimmune disorders in a multisite study of probands with childhood-onset obsessive compulsive disorder (OCD) and their first-degree relatives. Methods: Medical questionnaires were completed by 1401 probands and 1045 first-degree relatives in the OCD Collaborative Genetics Association Study. Lifetime prevalence of immune-related diseases was compared with the highest available population estimate and reported as a point estimate with 95% adjusted Wald interval. Worst-episode OCD severity and symptom dimensions were assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Symptom Checklist (YBOCS-CL). Results: Probands reported higher-than-expected prevalence of scarlet fever (4.0 [3.1-5.2]% vs. 1.0%-2.0%, z = 1.491, p < 0.001, n = 1389), encephalitis or meningitis (1.4 [0.9-2.1]% vs. 0.1%-0.4%, z = 5.913, p < 0.001, n = 1393), rheumatoid arthritis (1.1 [0.6-2.0]% vs. 0.2%-0.4%, z = 3.416, p < 0.001, n = 949) and rheumatic fever (0.6 [0.3-1.2]% vs. 0.1%-0.2%, z = 3.338, p < 0.001, n = 1390), but not systemic lupus erythematosus, diabetes, asthma, multiple sclerosis, psoriasis, or inflammatory bowel disease. First-degree relatives reported similarly elevated rates of scarlet fever, rheumatic fever, and encephalitis or meningitis independent of OCD status. There was no association between worst-episode severity and immune-related comorbidities, although probands reporting frequent ear or throat infections had increased severity of cleaning-/contamination-related symptoms (mean factor score 2.5 ± 0.9 vs. 2.3 ± 1.0, t = 3.183, p = 0.002, n = 822). Conclusion: These data suggest high rates of streptococcal-related and other immune-mediated diseases in patients with childhood-onset OCD and are consistent with epidemiological studies in adults noting familial clustering. Limitations include potential reporting bias and absence of a control group, underscoring the need for further prospective studies characterizing medical and psychiatric disease clusters and their interactions in children. Such studies may ultimately improve our understanding of OCD pathogenesis and aid in the development of adjunctive immune-modulating therapeutic strategies.

Robust Reference Powered Association Test of Genome-Wide Association Studies.

Genome-wide association studies (GWASs) have identified abundant genetic susceptibility loci, GWAS of small sample size are far less from meeting the previous expectations due to low statistical power and false positive results. Effective statistical methods are required to further improve the analyses of massive GWAS data. Here we presented a new statistic (Robust Reference Powered Association Test) to use large public database (gnomad) as reference to reduce concern of potential population stratification. To evaluate the performance of this statistic for various situations, we simulated multiple sets of sample size and frequencies to compute statistical power. Furthermore, we applied our method to several real datasets (psoriasis genome-wide association datasets and schizophrenia genome-wide association dataset) to evaluate the performance. Careful analyses indicated that our newly developed statistic outperformed several previously developed GWAS applications. Importantly, this statistic is more robust than naive merging method in the presence of small control-reference differentiation, therefore likely to detect more association signals.

Correction: Exploratory genome-wide association analysis of response to ketamine and a polygenic analysis of response to scopolamine in depression.

Michael F. Grunebaum's name was misspelled/misstated as "Gruenbaum M.F." in the original Article. This has now been updated in the HTML and PDF versions of this Article.

Exploratory genome-wide association analysis of response to ketamine and a polygenic analysis of response to scopolamine in depression.

Growing evidence suggests that the glutamatergic modulator ketamine has rapid antidepressant effects in treatment-resistant depressed subjects. The anticholinergic agent scopolamine has also shown promise as a rapid-acting antidepressant. This study applied genome-wide markers to investigate the role of genetic variants in predicting acute antidepressant response to both agents. The ketamine-treated sample included 157 unrelated European subjects with major depressive disorder (MDD) or bipolar disorder (BD). The scopolamine-treated sample comprised 37 unrelated European subjects diagnosed with either MDD or BD who had a current Major Depressive Episode (MDE), and had failed at least two adequate treatment trials for depression. Change in Montgomery-Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) scale scores at day 1 (24 h post-treatment) was considered the primary outcome. Here, we conduct pilot genome-wide association study (GWAS) analyses to identify potential markers of ketamine response and dissociative side effects. Polygenic risk score analysis of SNPs ranked by the strength of their association with ketamine response was then calculated in order to assess whether common genetic markers from the ketamine study could predict response to scopolamine. Findings require replication in larger samples in light of low power of analyses of these small samples. Neverthless, these data provide a promising illustration of our future potential to identify genetic variants underlying rapid treatment response in mood disorders and may ultimately guide individual patient treatment selection in the future.

knnAUC: an open-source R package for detecting nonlinear dependence between one continuous variable and one binary variable.

BACKGROUND: Testing the dependence of two variables is one of the fundamental tasks in statistics. In this work, we developed an open-source R package (knnAUC) for detecting nonlinear dependence between one continuous variable X and one binary dependent variables Y (0 or 1). RESULTS: We addressed this problem by using knnAUC (k-nearest neighbors AUC test, the R package is available at https://sourceforge.net/projects/knnauc/ ). In the knnAUC software framework, we first resampled a dataset to get the training and testing dataset according to the sample ratio (from 0 to 1), and then constructed a k-nearest neighbors algorithm classifier to get the yhat estimator (the probability of y = 1) of testy (the true label of testing dataset). Finally, we calculated the AUC (area under the curve of receiver operating characteristic) estimator and tested whether the AUC estimator is greater than 0.5. To evaluate the advantages of knnAUC compared to seven other popular methods, we performed extensive simulations to explore the relationships between eight different methods and compared the false positive rates and statistical power using both simulated and real datasets (Chronic hepatitis B datasets and kidney cancer RNA-seq datasets). CONCLUSIONS: We concluded that knnAUC is an efficient R package to test non-linear dependence between one continuous variable and one binary dependent variable especially in computational biology area.

Decreased Gray Matter Volume of Cuneus and Lingual Gyrus in Schizophrenia Patients with Tardive Dyskinesia is Associated with Abnormal Involuntary Movement.

Tardive dyskinesia (TD) is a devastating motor disorder associated with the etiological process of schizophrenia or antipsychotic medication treatments. To examine whether cerebral morphological changes may manifest in TD, we used voxel-based morphometry to analyze high-resolution T1-weighted brain structural magnetic resonance images from 32 schizophrenics with TD (TD group), 31 schizophrenics without TD (non-TD group), and 32 healthy controls (HC group). We also assessed psychopathological symptoms with the Positive and Negative Syndrome Scale (PANSS), and TD severity with the Abnormal Involuntary Movement Scale (AIMS). We compared gray matter volumes (GMVs) among groups, and tested for correlations between GMV changes and psychopathological symptoms or TD severity. The results showed significant differences in GMV in the frontal and temporal cortices, insula and cerebellum among the three groups. Brainstem and inferior frontal and precentral gyri GMVs were significantly larger, whereas cuneus and lingual gyrus GMVs were significantly smaller in the TD group as compared to non-TD group. Further, the cuneus and lingual gyrus GMVs were positively correlated with AIMS scores in the TD group. The current results suggest that TD may be associated with the alterations in GMV that are different from that of schizophrenics without TD. Further studies are needed to confirm and to examine the functional significance of these structural findings.

Nuclear Norm Clustering: a promising alternative method for clustering tasks.

Clustering techniques are widely used in many applications. The goal of clustering is to identify patterns or groups of similar objects within a dataset of interest. However, many cluster methods are neither robust nor sensitive to noises and outliers in real data. In this paper, we present Nuclear Norm Clustering (NNC, available at https://sourceforge.net/projects/nnc/), an algorithm that can be used in various fields as a promising alternative to the k-means clustering method. The NNC algorithm requires users to provide a data matrix M and a desired number of cluster K. We employed simulated annealing techniques to choose an optimal label vector that minimizes nuclear norm of the pooled within cluster residual matrix. To evaluate the performance of the NNC algorithm, we compared the performance of both 15 public datasets and 2 genome-wide association studies (GWAS) on psoriasis, comparing our method with other classic methods. The results indicate that NNC method has a competitive performance in terms of F-score on 15 benchmarked public datasets and 2 psoriasis GWAS datasets. So NNC is a promising alternative method for clustering tasks.

Self-reported executive function and hoarding in adults with obsessive-compulsive disorder.

BACKGROUND: Hoarding behavior may distinguish a clinically and possibly etiologically distinct subtype of obsessive-compulsive disorder (OCD). Little is known about the relationship between executive dysfunction and hoarding in individuals with OCD. METHODS: The study sample included 431 adults diagnosed with DSM-IV OCD. Participants were assessed by clinicians for Axis I disorders, personality disorders, indecision, and hoarding. Executive functioning domains were evaluated using a self-report instrument, the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). We compared scores on these domains in the 143 hoarding and 288 non-hoarding participants, separately in men and women. We used logistic regression to evaluate relationships between executive function scores and hoarding, and correlation and linear regression analyses to evaluate relationships between executive function scores and hoarding severity, in women. RESULTS: In men, the hoarding group had a significantly higher mean score than the non-hoarding group only on the shift dimension. In contrast, in women, the hoarding group had higher mean scores on the shift scale and all metacognition dimensions, i.e., those that assess the ability to systematically solve problems via planning and organization. The relationships in women between hoarding and scores on initiating tasks, planning/organizing, organization of materials, and the metacognition index were independent of other clinical features. Furthermore, the severity of hoarding in women correlated most strongly with metacognition dimensions. CONCLUSIONS: Self-reported deficits in planning and organization are associated with the occurrence and severity of hoarding in women, but not men, with OCD. This may have implications for elucidating the etiology of, and developing effective treatments for, hoarding in OCD.

Diagnostic value of blood-derived microRNAs for schizophrenia: results of a meta-analysis and validation.

There is an increasing interest in searching biomarkers for schizophrenia (SZ) diagnosis, which overcomes the drawbacks inherent with the subjective diagnostic methods. MicroRNA (miRNA) fingerprints have been explored for disease diagnosis. We performed a meta-analysis to examine miRNA diagnostic value for SZ and further validated the meta-analysis results. Using following terms: schizophrenia/SZ, microRNA/miRNA, diagnosis, sensitivity and specificity, we searched databases restricted to English language and reviewed all articles published from January 1990 to October 2016. All extracted data were statistically analyzed and the results were further validated with peripheral blood mononuclear cells (PBMNCs) isolated from patients and healthy controls using RT-qPCR and receiver operating characteristic (ROC) analysis. A total of 6 studies involving 330 patients and 202 healthy controls were included for meta-analysis. The pooled sensitivity, specificity and diagnostic odds ratio were 0.81 (95% CI: 0.75-0.86), 0.81 (95% CI: 0.72-0.88) and 18 (95% CI: 9-34), respectively; the positive and negative likelihood ratio was 4.3 and 0.24 respectively; the area under the curve in summary ROC was 0.87 (95% CI: 0.84-0.90). Validation revealed that miR-181b-5p, miR-21-5p, miR-195-5p, miR-137, miR-346 and miR-34a-5p in PBMNCs had high diagnostic sensitivity and specificity in the context of schizophrenia. In conclusion, blood-derived miRNAs might be promising biomarkers for SZ diagnosis.

Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia.

Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive. We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN, p.S2506T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations (CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.

Genome Wide Association Study (GWAS) between Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD).

Objective: The aim of this study was to identify any potential genetic overlap between attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). We hypothesized that since these disorders share a sub-phenotype, they may share common risk alleles. In this manuscript, we report the overlap found between these two disorders. Methods: A meta-analysis was conducted between ADHD and OCD, and polygenic risk scores (PRS) were calculated for both disorders. In addition, a protein-protein analysis was completed in order to examine the interactions between proteins; p-values for the protein-protein interaction analysis was calculated using permutation. Conclusion: None of the single nucleotide polymorphisms (SNPs) reached genome wide significance and there was little evidence of genetic overlap between ADHD and OCD.

An investigation of doubt in obsessive-compulsive disorder.

BACKGROUND: Clinicians have long considered doubt to be a fundamental characteristic of obsessive-compulsive disorder (OCD). However, the clinical relevance of doubt in OCD has not been addressed. METHODS: Participants included 1182 adults with OCD who had participated in family and genetic studies of OCD. We used a clinical measure of the severity of doubt, categorized as none, mild, moderate, severe, or extreme. We evaluated the relationship between doubt and OCD clinical features, Axis I disorders, personality and personality disorder dimensions, impairment, and treatment response. RESULTS: The severity of doubt was inversely related to the age at onset of OCD symptoms. Doubt was strongly related to the number of checking symptoms and, to a lesser extent, to the numbers of contamination/cleaning and hoarding symptoms. Doubt also was related to the lifetime prevalence of recurrent major depression and generalized anxiety disorder; to the numbers of avoidant, dependent, and obsessive-compulsive personality disorder traits; and to neuroticism and introversion. Moreover, doubt was strongly associated with global impairment and poor response to cognitive behavioral treatment (CBT), even adjusting for OCD severity and other correlates of doubt. CONCLUSIONS: Doubt is associated with important clinical features of OCD, including impairment and cognitive-behavioral treatment response.

ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is characterized by heterogeneous genetic and epigenetic changes. Recently, A-to-I RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), was found to be aberrantly regulated during tumorigenesis. We previously reported that ADAR2 was downregulated in ESCC but its role was unclear. Thus, we report here that overexpression of ADAR2 can induce apoptosis in ESCC cell lines and inhibit tumor growth in vitro and in vivo. ADAR2 knockdown inhibited apoptosis in ADAR2 highly expressing tumor cells. RNA-seq assay showed that ADAR2, not ADAR1 or active-site-mutated ADAR2, could edit insulin-like growth factor binding protein 7 (IGFBP7) mRNA in ESCC. IGFBP7 knockdown or ADAR2 catalytic activity destruction abolished the pro-apoptotic function of ADAR2. Mechanistically, RNA editing may stabilize IGFBP7 protein by changing the protease recognition site of matriptase and this is essential for IGFBP7 to induce apoptosis. Western blotting revealed that ADAR2 overexpression could induce IGFBP7-dependent inhibition of Akt signaling. Thus, our data indicate that ADAR2 suppresses tumor growth and induces apoptosis by editing and stabilizing IGFBP7 in ESCC, and this may represent a novel therapeutic target for treating ESCC.

Parental bonding and hoarding in obsessive-compulsive disorder.

BACKGROUND: Hoarding behavior may indicate a clinically and possibly etiologically distinct subtype of obsessive-compulsive disorder (OCD). Empirical evidence supports a relationship between hoarding and emotional over-attachment to objects. However, little is known about the relationship between hoarding and parental attachment in OCD. METHOD: The study sample included 894 adults diagnosed with DSM-IV OCD who had participated in family and genetic studies of OCD. Participants were assessed for Axis I disorders, personality disorders, and general personality dimensions. The Parental Bonding Instrument (PBI) was used to assess dimensions of perceived parental rearing (care, overprotection, and control). We compared parental PBI scores in the 334 hoarding and 560 non-hoarding participants, separately in men and women. We used logistic regression to evaluate the relationship between parenting scores and hoarding in women, adjusting for other clinical features associated with hoarding. RESULTS: In men, there were no significant differences between hoarding and non-hoarding groups in maternal or paternal parenting scores. In women, the hoarding group had a lower mean score on maternal care (23.4 vs. 25.7, p<0.01); a higher mean score on maternal protection (9.4 vs. 7.7, p<0.001); and a higher mean score on maternal control (7.0 vs. 6.2, p<0.05), compared to the non-hoarding group. The magnitude of the relationships between maternal bonding dimensions and hoarding in women did not change after adjustment for other clinical features. Women who reported low maternal care/high maternal protection had significantly greater odds of hoarding compared to women with high maternal care/low maternal protection (OR=2.54, 95% CI=1.60-4.02, p<0.001). CONCLUSIONS: Perceived poor maternal care, maternal overprotection, and maternal overcontrol are associated with hoarding in women with OCD. Parenting dimensions are not related to hoarding in men. These findings provide further support for a hoarding subtype of OCD and for sex-specific differences in etiologic pathways for hoarding in OCD.

Integrating multiple genomic data: sparse representation based biomarker selection for blood pressure.

BACKGROUND: Although many genes have been implicated as hypertension candidates, to date, few studies have integrated different types of genomic data for the purpose of biomarker selection. METHODS: Applying a newly proposed sparse representation based variable selection (SRVS) method to the Genetic Analysis Workshop19 data, we analyzed a combined data set consisting of 11522 gene expressions and 354893 single-nucleotide polymorphisms (SNPs) from 397 subjects (case/control: 151/246), with the aim to identify potential biomarkers for blood pressure using both gene expression measures and SNP data. RESULTS: Among the top 1000 variables (SNPs/gene expressions = 575/425) selected, the bioinformatics analysis showed that 302 were plausibly associated with blood pressure. In addition, we identified 173 variables that were associated with body weight and 84 associated with left ventricular contractility. Together, 55.9 % of the top 1000 variables showed associations with blood pressure related phenotypes(SNP/gene expression =348/211). CONCLUSIONS: Our results support the feasibility of the SRVS algorithm in integrating multiple data sets of different structure for comprehensive analysis.

ADHD and executive functioning deficits in OCD youths who hoard.

Hoarding is common among youth with obsessive compulsive disorder (OCD), with up to 26% of OCD youth exhibiting hoarding symptoms. Recent evidence from adult hoarding and OCD cohorts suggests that hoarding symptoms are associated with executive functioning deficits similar to those observed in subjects with attention deficit hyperactivity disorder (ADHD). However, while hoarding behavior often onsets during childhood, there is little information about executive function deficits and ADHD in affected children and adolescents. The study sample included 431 youths (ages 6-17 years) diagnosed with OCD who participated in the OCD Collaborative Genetics Study and the OCD Collaborative Genetics Association Study and completed a series of clinician-administered and parent report assessments, including diagnostic interviews and measures of executive functioning (Behavior Rating Inventory of Executive Functioning; BRIEF) and hoarding severity (Hoarding Rating Scale-Interview; HRS-I). 113 youths (26%) had clinically significant levels of hoarding compulsions. Youths with and without hoarding differed significantly on most executive functioning subdomains and composite indices as measured by the parent-rated BRIEF. Groups did not differ in the frequency of full DSM-IV ADHD diagnoses; however, the hoarding group had significantly greater number of inattention and hyperactivity symptoms compared to the non-hoarding group. In multivariate models, we found that overall BRIEF scores were related to hoarding severity, adjusting for age, gender and ADHD symptoms. These findings suggest an association between hoarding and executive functioning deficits in youths with OCD, and assessing executive functioning may be important for investigating the etiology and treatment of children and adolescents with hoarding and OCD.

Random Bits Forest: a Strong Classifier/Regressor for Big Data.

Efficiency, memory consumption, and robustness are common problems with many popular methods for data analysis. As a solution, we present Random Bits Forest (RBF), a classification and regression algorithm that integrates neural networks (for depth), boosting (for width), and random forests (for prediction accuracy). Through a gradient boosting scheme, it first generates and selects ~10,000 small, 3-layer random neural networks. These networks are then fed into a modified random forest algorithm to obtain predictions. Testing with datasets from the UCI (University of California, Irvine) Machine Learning Repository shows that RBF outperforms other popular methods in both accuracy and robustness, especially with large datasets (N > 1000). The algorithm also performed highly in testing with an independent data set, a real psoriasis genome-wide association study (GWAS).

Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis.

The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.

Evidence for contribution of common genetic variants within chromosome 8p21.2-8p21.1 to restricted and repetitive behaviors in autism spectrum disorders.

BACKGROUND: Restricted and Repetitive Behaviors (RRB), one of the core symptom categories for Autism Spectrum Disorders (ASD), comprises heterogeneous groups of behaviors. Previous research indicates that there are two or more factors (subcategories) within the RRB domain. In an effort to identify common variants associated with RRB, we have carried out a genome-wide association study (GWAS) using the Autism Genetic Resource Exchange (AGRE) dataset (n = 1,335, all ASD probands of European ancestry) for each identified RRB subcategory, while allowing for comparisons of associated single nucleotide polymorphisms (SNPs) with associated SNPs in the same set of probands analyzed using all the RRB subcategories as phenotypes in a multivariate linear mixed model. The top ranked SNPs were then explored in an independent dataset. RESULTS: Using principal component analysis of item scores obtained from Autism Diagnostic Interview-Revised (ADI-R), two distinct subcategories within Restricted and Repetitive Behaviors were identified: Repetitive Sensory Motor (RSM) and Insistence on Sameness (IS). Quantitative RSM and IS scores were subsequently used as phenotypes in a GWAS using the AGRE ASD cohort. Although no associated SNPs with genome-wide significance (P < 5.0E-08) were detected when RSM or IS were analyzed independently, three SNPs approached genome-wide significance when RSM and IS were considered together using multivariate association analysis. These included the top IS-associated SNP, rs62503729 (P-value = 6.48E-08), which is located within chromosome 8p21.2-8p21.1, a locus previously linked to schizophrenia. Notably, all of the most significantly associated SNPs are located in close proximity to STMN4 and PTK2B, genes previously shown to function in neuron development. In addition, several of the top-ranked SNPs showed correlations with STMN4 mRNA expression in adult CEU (Caucasian and European descent) human prefrontal cortex. However, the association signals within chromosome 8p21.2-8p21.1 failed to replicate in an independent sample of 2,588 ASD probands; the insufficient sample size and between-study heterogeneity are possible explanations for the non-replication. CONCLUSIONS: Our analysis indicates that RRB in ASD can be represented by two distinct subcategories: RSM and IS. Subsequent univariate and multivariate genome-wide association studies of these RRB subcategories enabled the detection of associated SNPs at 8p21.2-8p21.1. Although these results did not replicate in an independent ASD dataset, genomic features of this region and pathway analysis suggest that common variants in 8p21.2-8p21.1 may contribute to RRB, particularly IS. Together, these observations warrant future studies to elucidate the possible contributions of common variants in 8p21.2-8p21.1 to the etiology of RSM and IS in ASD.