Biology subjects

Mulle, J. G.

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

3 recordsLinked to original sources

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↗