Biology subjects

Mulle, J. G.

Publications and source records attributed to Mulle, J. G..

17 recordsLinked to original sources

bioRxiv2026

Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome

22q11.2 Deletion Syndrome (22q11DS), the most prevalent chromosomal microdeletion disorder in humans (incidence ~1 in 4,000 live births), arises from hemizygous deletions of a 1.5-3.0 Mb region on chromosome 22. Notably, 20-30% of individuals with 22q11DS develop schizophrenia (SCZ) by early adulthood, making 22q11DS one of the strongest genetic risk factors for SCZ. However, the mechanisms by which the 22q11.2 deletion perturbs neuronal function and drive psychotic manifestations in 22q11DS remain poorly defined. In this study, we generated human 2D cortical neurons and 3D cortical organoids from induced pluripotent stem cells (iPSCs) derived from clinically well-characterized individuals with 22q11DS. Cellular and electrophysiological analyses revealed that 22q11DS neurons exhibit hyperexcitability, reduced glutamatergic synaptic transmission, and impaired homeostatic synaptic plasticity, which are pathophysiological hallmarks that may be relevant to the clinical, cognitive, and psychophysiological profiles of patients. Transcriptomic profiling of neurons and synaptosomes from 22q11DS cortical organoids uncovered dysregulated immune pathways and synaptic gene networks. Integrative mRNA-microRNA network analysis identified synergistic downregulation of hsa-miR-185-5p and hsa-miR-128-3p at synapses, driving aberrant regulation of immune and synaptic transcripts. Experimental knockdown of these microRNAs in control neurons recapitulated the molecular and functional phenotypes of 22q11DS neurons, thereby establishing a mechanistic link to synaptic dysfunction and impaired plasticity. Collectively, these findings delineate a multimodal mechanistic framework that bridges genetic vulnerability, synaptic pathology, and psychosis penetrance in 22q11DS, positioning dysregulated synaptic microRNAs as nodal regulators of neurodevelopmental networks and potential therapeutic targets.

neuroscience↗

bioRxiv2026

Cerebellar mitochondrial dysfunction coincides with structural and behavioral abnormalities in 3q29Del mice

3q29 deletion (3q29Del) is a genetic risk variant for autism spectrum disorder and schizophrenia that often results in developmental delays, cognitive disability, and impaired fine motor function. People with 3q29Del have reduced cerebellar volume, which correlates with symptom severity, and many 3q29Del-associated phenotypes also commonly occur after cerebellar injury or dysfunction. However, it is unknown whether the existing 3q29Del mouse model recapitulates the cerebellar dysfunction observed in humans. To characterize cerebellar phenotypes and uncover pathological differences in the 3q29Del mouse model, we investigated cerebellar structure, motor and vocal behaviors, protein expression, and mitochondrial function. We found uniformly reduced cerebellar volume in 3q29Del mice. Behavioral assays revealed vocal impairments in 3q29Del pups, fine motor impairments in adult mice, and reduced social mating calls in adult male mice. Proteomic analysis revealed enrichment of synaptic and mitochondrial proteins among the differentially expressed proteins in 3q29Del cerebellum tissue. Furthermore, mitochondria from 3q29Del mouse cerebellum displayed reduced oxygen flux and increased electron leak. These results recapitulate many human 3q29Del phenotypes in the 3q29Del mouse model and indicate mitochondrial dysfunction as a potential driver of 3q29Del pathology. Our findings also point to cerebellar involvement in 3q29Del phenotypes and provide a foundation for further research on cerebellar development in 3q29Del.

neuroscience↗

bioRxiv2026

Genetic insights on the mechanisms of human cortical folding

The unique and intricate pattern of human cortical folding is rooted in fetal neurodevelopmental processes and can now be comprehensively quantified by new neuroimaging-derived measures of sulcal complexity. Here, we provide the first genetic maps of human sulcal complexity. Beginning with large effects of rare variants, we survey nine different neurogenetic syndromes (n=615), detecting visible changes in sulcal complexity on a shared axis of sulcal change coupled to the prenatal timing of sulcation. Turning to common genetic variants, we use genome-wide association studies of complexity scores for 40 sulci in the UK Biobank (n[~]29,000) to (i) resolve variable heritability across sulci, (ii) reveal both local and remote shared genetic effects with cortical morphology, and (iii) identify complexity-associated genes and their embedding in brain maps of prenatal gene expression. These reference genetic maps uncover multiple new mechanistic pathways for cortical morphogenesis in health and disease.

neuroscience↗

bioRxiv2026

Female iPSC X-chromosome inactivation (XCI) erosion and its transcriptomic effects during CRISPR gene editing and neural differentiation

Human induced pluripotent stem cells (hiPSC) and iPSC-differentiated neural cells, in combination with CRISPR editing, are commonly used for studying neurodevelopmental and other brain disorders. Female iPSCs undergo random X-chromosome inactivation (XCI) via epigenetic silencing by noncoding X inactive specific transcript (XIST). It is known that female iPSCs may lose XIST expression, leading to XCI erosion that affects both X-linked and autosomal gene expression. However, the effects of CRSIPR editing and neural differentiation on XCI erosion in iPSC-derived neurons and how this may confound a real-world transcriptomic analysis of differentially expressed genes (DEGs) are poorly understood. Here, leveraging bulk RNA-seq of hundreds of CRISPR-edited female iPSC lines from four donor lines for 66 genes and single-cell RNA-seq of iPSC-derived neurons of a subset of 42 edited genes, we investigated the effects of XCI erosion during CRISPR editing and in iPSC-derived neurons. We found that XCI erosion was variable in CRISPR-edited female iPSCs and largely preserved in iPSC-derived neurons. Like in iPSCs, XIST in neurons predominately influenced the expression of X-linked genes; however, its effect on autosomal genes was more pronounced in single neurons. Mechanistically, XIST epigenetically causes allelic imbalance of both X-linked and autosomal genes, with the former showing stronger allele-specific expression (ASE) bias. Notably, XIST-induced ASE bias exhibited a conserved positional pattern at loci affecting neurodevelopmental genes across different female lines and cell types. Finally, we demonstrated a confounding effect of XCI erosion on DEG analyses in iPSC-derived neurons. These results have significant implications in hiPSC modeling of neurodevelopmental and other brain disorders.

genomics↗

bioRxiv2026

Convergent effects of neurodevelopmental disorder-associated variants at mitochondria

Investigations into the molecular pathogenesis of clinically defined neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD) and schizophrenia (SCZ) have produced evidence implicating dysfunctional mitochondrial metabolism. However, the functional connection between risk variants and mitochondrial proteins largely remains unclear. We tested the hypothesis that proteins encoded by NDD-associated copy number variants (CNVs) and SCZ risk genes are enriched within the mitochondrial interactome. We found that NDD- and SCZ-associated genes exhibit mitochondrial association comparable to their overlap with synaptic proteins, with interaction networks converging most strongly on mitochondrial translation. Two high-risk CNVs, the 3q29 deletion (3q29Del) and the 22q11.2 deletion (22q11Del), confer similar risks for ASD and SCZ and have independently been linked to mitochondrial phenotypes. To test whether these CNVs produce convergent effects on mitochondrial proteins in developing human neural tissue, we generated an isogenic series of 3q29Del and 22q11Del induced-pluripotent stem cells (iPSCs) and differentiated them into forebrain cortical organoids. Quantitative proteomic analysis showed high similarity in the profiles of dysregulated proteins in 3q29Del and 22q11Del compared to isogenic controls. Enrichment analysis of proteins altered in both variants revealed significant convergence on the mitochondrial ribosome and translation machinery. Furthermore, manipulation of mitochondrial translation elicited similar proteomic and functional responses in organoids and neural progenitor cells across both CNVs. These findings indicate that NDD-associated genes have rich interactions with mitochondrial proteins and that two of the strongest risk factors for NDDs may similarly disrupt neural mitochondrial metabolism through impaired mitochondrial translation.

neuroscience↗

bioRxiv2024

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC

Translating genetic findings for neurodevelopmental and psychiatric disorders (NPD) into actionable disease biology would benefit from large-scale and unbiased functional studies of NPD genes. Leveraging the cytosine base editing (CBE) system, here we developed a pipeline for clonal loss-of-function (LoF) allele mutagenesis in human induced pluripotent stem cells (hiPSCs) by introducing premature stop-codons (iSTOP) that lead to mRNA nonsense-mediated-decay (NMD) or protein truncation. We tested the pipeline for 23 NPD genes on 3 hiPSC lines and achieved highly reproducible, efficient iSTOP editing in 22 NPD genes. Using RNAseq, we confirmed their pluripotency, absence of chromosomal abnormalities, and NMD. Interestingly, for three schizophrenia risk genes (SETD1A, TRIO, CUL1), despite the high efficiency of base editing, we only obtained heterozygous LoF alleles, suggesting their essential roles for cell growth. We replicated the reported neural phenotypes of SHANK3-haploinsufficiency and found CUL1-LoF reduced neurite branches and synaptic puncta density. This iSTOP pipeline enables a scaled and efficient LoF mutagenesis of NPD genes, yielding an invaluable shareable resource.

genetics↗

bioRxiv2023

Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Recent advances in the genetics of schizophrenia (SCZ) have identified rare variants that confer high disease risk, including a 1.6 Mb deletion at chromosome 3q29 with a staggeringly large effect size (O.R. > 40). Understanding the impact of the 3q29 deletion (3q29Del) on the developing CNS may therefore lead to insights about the pathobiology of schizophrenia. To gain clues about the molecular and cellular perturbations caused by the 3q29 deletion, we interrogated transcriptomic effects in two experimental model systems with complementary advantages: isogenic human forebrain cortical organoids and isocortex from the 3q29Del mouse model. We first created isogenic lines by engineering the full 3q29Del into an induced pluripotent stem cell line from a neurotypical individual. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 months and 12 months, as well as day p7 perinatal mouse isocortex, all at single cell resolution. Differential expression analysis by genotype in each cell-type cluster revealed that more than half of the differentially expressed genes identified in mouse cortex were also differentially expressed in human cortical organoids, and strong correlations were observed in mouse-human differential gene expression across most major cell-types. We systematically filtered differentially expressed genes to identify changes occurring in both model systems. Pathway analysis on this filtered gene set implicated dysregulation of mitochondrial function and energy metabolism, although the direction of the effect was dependent on developmental timepoint. Transcriptomic changes were validated at the protein level by analysis of oxidative phosphorylation protein complexes in mouse brain tissue. Assays of mitochondrial function in human heterologous cells further confirmed robust mitochondrial dysregulation in 3q29Del cells, and these effects are partially recapitulated by ablation of the 3q29Del gene PAK2. Taken together these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species. These results converge with data from other rare SCZ-associated variants as well as idiopathic schizophrenia, suggesting that mitochondrial dysfunction may be a significant but overlooked contributing factor to the development of psychotic disorders. This cross-species scRNA-seq analysis of the SCZ-associated 3q29 deletion reveals that this copy number variant may produce early and persistent changes in cellular metabolism that are relevant to human neurodevelopment.

genomics↗

bioRxiv2022

Visual-motor integration deficits in 3q29 deletion syndrome

Purpose3q29 deletion syndrome (3q29del) is associated with neuropsychiatric and neurodevelopmental phenotypes. We previously reported that graphomotor weakness is present in up to 78% of individuals with 3q29del. We have now explored nuances of the graphomotor phenotype and its association with other comorbidities in this population. MethodsParticipants were recruited from the online 3q29 registry (3q29deletion.org) for two days of deep phenotyping. 32 individuals with 3q29del (62.5% male) were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) to assess visual-motor integration. Participants were also evaluated with measures of cognitive ability, executive function, adaptive behavior, and school function. ResultsMales with 3q29del performed significantly worse than females on the VMI and Motor Coordination subtest. VMI performance was significantly associated with ADHD diagnosis and cognitive ability. Compared to published data from individuals with 22q11.2 deletion syndrome, individuals with 3q29del showed significantly more impairment. ConclusionThe 3q29 deletion is associated with substantial deficits in visual-motor integration, Visual Perception, and Motor Coordination. Our data suggests that 3q29del may qualify as a nonverbal learning disability, and that all individuals with 3q29del may benefit from early interventions, including occupational therapy.

genetics↗

bioRxiv2022

Loss-of-function of OTUD7A in the schizophrenia-associated 15q13.3 deletion impairs synapse development and function in human neurons

Identifying causative gene(s) within disease-associated large genomic regions of copy number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases, but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR/Cas9 engineering. The mutant iNs showed a [~]50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function, and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.

neuroscience↗

bioRxiv2020

Metabolic effects of the schizophrenia-associated 3q29 deletion are sex-specific and uncoupled from behavioral phenotypes

The 1.6 Mb 3q29 deletion is associated with developmental and psychiatric phenotypes. Reduced birthweight and a high prevalence of feeding disorders in patients suggest underlying metabolic dysregulation. We investigated 3q29 deletion-induced metabolic changes using the B6.Del16+/Bdh1-Tfrc mouse model. We found that B6.Del16+/Bdh1-Tfrc animals preferentially use dietary lipids as an energy source. Untargeted metabolomics showed a strong sex-dependent effect of the 3q29 deletion on fat metabolism. A high-fat diet (HFD) partially rescued the 3q29 deletion-associated weight deficit in females, but not males. Untargeted metabolomics after HFD revealed persistent fat metabolism alterations in females. The HFD did not affect B6.Del16+/Bdh1-Tfrc behavioral phenotypes, suggesting that 3q29 deletion-associated metabolic and behavioral outcomes are uncoupled. Our data indicate a HFD intervention in 3q29 deletion syndrome may improve weight phenotypes without exacerbating behavioral manifestations. Our study also highlights the importance of assessing sex in metabolic studies and suggests mechanisms underlying 3q29 deletion-associated metabolic phenotypes are sex-specific.

genetics↗

bioRxiv2020

Sex-specific recombination predicts parent of origin for recurrent genomic disorders

Genomic disorders are caused by structural rearrangements of the genome that generally occur during meiosis1. Often the rearrangements result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications [≥] 1 kb)2,3. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR)3,4. Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs5-9. However, the mechanism underlying these biases is not well understood. Here we have curated parent of origin data for multiple pathogenic CNV loci and demonstrate a significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci. Our results suggest that parental-origin of CNVs is largely controlled by sex-specific recombination rates and bring into light the need to consider these differences when seeking to determine the factors underlying risk for structural variation.

genetics↗

bioRxiv2020

Convergent and distributed effects of the schizophrenia-associated 3q29 deletion on the human neural transcriptome

The 3q29 deletion (3q29Del) confers >40-fold increased risk for schizophrenia. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, post-translational modifications, chromatin remodeling and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging "guilt by association", we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological post-mortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.

genetics↗

bioRxiv2019

Systematic Description of 3q29 Duplication Syndrome Reveals New Syndromic Phenotypes: Results from the 3q29 Registry

3q29 duplication syndrome (3q29Dup) is a rare genomic disorder caused by the reciprocal duplication of the 1.6 Mb 3q29 deletion syndrome region. Case reports indicate the 3q29Dup is likely to be pathogenic, but because no systematic study of the syndrome exists, the full range of manifestations is not well-understood. To develop a better understanding of 3q29 duplication syndrome, we used the 3q29 registry (https://3q29deletion.patientcrossroads.org/) to ascertain 31 individuals with 3q29Dup, the largest cohort ever surveyed in a systematic way. For comparison, we ascertained 117 individuals with the reciprocal 3q29 deletion syndrome (3q29Del) and 64 typically developing controls. We used a custom medical and demographic questionnaire to assess physical and developmental phenotypes, and two standardized instruments, the Social Responsiveness Scale (SRS) and Achenbach Behavior Checklists (CBCL/ABCL), to assess social disability. We find that our 3q29Dup participants report a high rate of problems in the first year of life (80.6%), including feeding problems (58%), failure to gain weight (42%), hypotonia (39%), and respiratory distress (29%). In early childhood, learning problems (87.1%) and seizures (25.8%) are common. Additionally, we find a rate of self-reported ASD diagnoses (39%) similar to that previously identified in 3q29Del (29%), and the granular characteristics of social disability measured using the SRS and CBCL/ABCL are comparable between 3q29Dup and 3q29Del. This is the most comprehensive description of 3q29Dup to date. Our findings can be used to develop evidence-based strategies for early intervention and management of 3q29 duplication syndrome.

genetics↗

bioRxiv2018

Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion

The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16. mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. Additionally, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1+/- mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sex-dependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.

genetics↗

bioRxiv2018

Neuropsychiatric Phenotypes in 3q29 Deletion Syndrome

BackgroundThe 1.6 Mb 3q29 deletion is associated with neurodevelopmental and psychiatric phenotypes, including increased risk for autism spectrum disorder (ASD) and a 20-40-fold increased risk for schizophrenia. However, the phenotypic spectrum of the deletion, particularly with respect to ASD, remains poorly described.\n\nMethodsWe ascertained individuals with 3q29 deletion syndrome (3q29Del, \"cases\", n=93, 58.1% male) and typically developing controls (n=64, 51.6% male) through the 3q29 registry (https://3q29deletion.patientcrossroads.org). Self-report of neuropsychiatric illness was evaluated for 93 cases. Subsets of participants were evaluated with the Social Responsiveness Scale (SRS, n=48 cases, 56 controls), Social Communication Questionnaire (SCQ, n=33 cases, 46 controls), Autism Spectrum Screening Questionnaire (ASSQ, n=24 cases, 35 controls), and Achenbach Behavior Checklists (n=48 cases, 57 controls).\n\nResults3q29Del cases report a higher prevalence of autism diagnoses versus the general population (29.0% vs. 1.47%, p<2.2E-16). Notably, 3q29 deletion confers a greater influence on risk for ASD in females (OR=41.8, p=4.78E-05) than in males (OR=24.6, p=6.06E-09); this is aligned with the reduced male:female bias from 4:1 in the general population to 2:1 in our study sample. Although 71% of cases do not report a diagnosis of ASD, there is evidence of significant social disability (3q29Del SRS T-score=71.8, control SRS T-score=45.9, p=2.16E-13). Cases also report increased frequency of generalized anxiety disorder compared to controls (28.0% vs. 6.2%, p=0.001), which is mirrored by elevated mean scores on the Achenbach DSM-oriented sub-scales (p<0.001). Finally, cases show a distinct constellation of ASD features on the SRS as compared to idiopathic ASD, with substantially elevated Restricted Interests and Repetitive Behaviors, but only mild impairment in Social Motivation.\n\nConclusionsOur sample of 3q29Del is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when an ASD diagnosis is not reported. Further, the constellation of ASD features in this population is distinct from idiopathic ASD, with substantially less impaired social motivation. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29Del. From a research perspective, the distinct ASD subtype present in 3q29Del is an ideal entry point for expanding understanding of ASD.

genetics↗

bioRxiv2018

Powerful and Efficient Strategies for Genetic Association Testing of Symptom and Questionnaire Data in Psychiatric Genetic Studies

Genetic studies of psychiatric disorders often deal with phenotypes that are not directly measurable. Instead, researchers rely on multivariate symptom data from questionnaires and surveys like the PTSD Symptom Scale (PSS) and Beck Depression Inventory (BDI) to indirectly assess a latent phenotype of interest. Researchers subsequently collapse such multivariate questionnaire data into a univariate outcome to represent a surrogate for the latent phenotype. However, when a causal variant is only associated with a subset of collapsed symptoms, the effect will be challenging to detect using the univariate outcome. We describe a more powerful strategy for genetic association testing in this situation that jointly analyzes the original multivariate symptom data collectively using a statistical framework that compares similarity in multivariate symptom-scale data from questionnaires to similarity in common genetic variants across a gene. We use simulated data to demonstrate this strategy provides substantially increased power over standard approaches that collapse questionnaire data into a single surrogate outcome. We also illustrate our approach using GWAS data from the Grady Trauma Project and identify genes associated with BDI not identified using standard univariate techniques. The approach is computationally efficient, scales to genome-wide studies, and is applicable to correlated symptom data of arbitrary dimension (thereby aligning with National Institute of Mental Healths Research Domain Criteria).

genetics↗

bioRxiv2016

Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects

One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2,000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: 1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and 2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD and 211 control individuals with DS and a normal heart using a custom microarray with dense probes tiled on chromosome 21 for array CGH. We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. Pathway analyses indicated copy number perturbations of genes involved in protein heterotrimerization and histone methylating proteins. Finally, we showed that previously DS+AVSD-associated common CNVs on chromosome 21 are likely false positives. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.

genomics↗