Showing papers by "Michael E. Zwick published in 2021"

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Abstract: Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Abstract: Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Site- and Taxa-Specific Disease-Associated Oral Microbial Structures Distinguish Inflammatory Bowel Diseases.

Abstract: Background The gut and oral microbiome have independently been shown to be associated with inflammatory bowel disease (IBD). However, it is not known to what extent gut and oral microbial disease markers converge in terms of their composition in IBD. Further, the spatial and temporal variation within the oral microenvironments of IBD remain to be elucidated. Patients and methods We used a prospectively recruited cohort of patients with IBD (n = 47) and unrelated healthy control patients (n = 18) to examine the spatial and temporal distribution of microbiota within the various oral microenvironments, represented by saliva, tongue, buccal mucosa, and plaque, and compared them with stool. Microbiome characterization was performed using 16S rRNA gene sequencing. Results The oral microbiome displayed IBD-associated dysbiosis, in a site- and taxa-specific manner. Plaque samples depicted a relatively severe degree of dysbiosis, and the disease-associated dysbiotic bacterial groups were predominantly the members of the phylum Firmicutes. Our 16S rRNA gene analyses show that oral microbiota can distinguish patients with IBD from healthy control patients, with salivary microbiota performing the best, closely matched by stool and other oral sites. Longitudinal profiles of microbial composition suggest that some taxa are more consistently perturbed than others, preferentially in a site-dependent fashion. Conclusions Collectively, these data indicate the potential of using oral microbial profiles in screening and monitoring patients with IBD. Furthermore, these results support the importance of spatial and longitudinal microbiome sampling to interpret disease-associated dysbiotic states and eventually to gain insights into disease pathogenesis.

Organizing core facilities as force multipliers: strategies for research universities.

Abstract: Force multipliers are attributes of an organization that enable the successful completion of multiple essential missions. Core facilities play a critical role in the research enterprise and can be organized as force multipliers. Conceiving of cores in this way influences their organization, funding, and research impact. To function as a force multiplier for the research enterprise, core facilities need to do more than efficiently provide services for investigators and generate revenue to recover their service costs: they must be aligned with the strategic objectives of a research university. When core facilities are organized in this way, they can facilitate recruitment of faculty and trainees; serve to retain talented faculty; drive, acquire, and maintain cutting-edge research platforms; and promote interaction and collaboration across the institution. Most importantly, cores accelerate the discovery and sharing of knowledge that are the foundation of a modern research university. This idea has been systematically implemented through the Emory Integrated Core Facilities (cores.emory.edu), which include 16 distinct core facilities and the Division of Animal Resources. Force multiplier core facilities can significantly contribute to the many essential missions necessary for the success of the research enterprise at research universities.

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease.

Abstract: Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.

Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders.

Abstract: Structural rearrangements of the genome, which generally occur during meiosis and result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb), underlie genomic disorders. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. We performed a systematic, comprehensive literature search to curate parent of origin data for multiple pathogenic CNV loci. Using a regression framework, we assessed the relationship between parental CNV origin and the male to female recombination rate ratio. We demonstrate significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci (p = 1.07 × 10–14). Our results suggest that parental origin of CNVs is largely influenced by sex-specific recombination rates and highlight the need to consider these differences when investigating mechanisms that cause structural variation.

Staff Scientist Perspectives on Onboarding and Professional Development: A Case Study.

Abstract: Across the United States, the number of staff scientists (master's- or doctoral-level professionals working in nonfaculty roles) has grown by 35% since 2010, and they play an increasingly important role in research efforts. However, few targeted resources are available, which potentially limits the effectiveness of this group. Launched in 2016, the staff scientist path at Emory has tripled in size over 4 y to 138 staff. The present case study evaluated the perceptions of staff scientists related to onboarding experiences and professional development needs, including those needs arising from coronavirus disease 2019 (COVID-19) impacts in the workplace. A survey of Emory staff scientists was conducted from May to June 2019 as part of a program evaluation initiative to assess perceptions of onboarding and professional development opportunities. Interviews with a subset of scientists informed the survey development and identified COVID-19-related impacts on daily work. Results indicated the need for targeted orientation resources specific to staff scientists, accurate and timely information and resources to support scientists' supervisors, and professional development for scientists in leadership and management-related skills. Remote work associated with COVID-19 accentuated the need for managerial skills, including team development in digital work environments. Findings from this case study can inform policies and practices at Emory and other institutions that employ a similar staff scientist model.