Faculty Bibliography
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The road ahead in genetics and genomics
In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.
PMCID:7444682
PMID: 32839576
ISSN: 1471-0064
CID: 4576222
Analysis of putative cis-regulatory elements regulating blood pressure variation
Hundreds of loci have been associated with blood pressure traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~ 100 000 Genetic Epidemiology Research on Aging (GERA) study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to blood pressure. We constructed maps of putative cis-regulatory elements using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative cis-regulatory elements within 50Kb of the start or end of 'expressed' genes in these tissues or cell types using public expression data, and use deltaSVM scores as weights in the group-wise sequence kernel association test (SKAT) to identify candidates. We test for association with both blood pressure traits and expression within these tissues or cell types of interest, and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B, and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study (ARIC), as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.
PMID: 32436959
ISSN: 1460-2083
CID: 4446962
MicroRNA-4516-mediated regulation of MAPK10 relies on 3' UTR cis-acting variants and contributes to the altered risk of Hirschsprung disease
BACKGROUND:in HSCR and how they contribute to the pathogenesis of HSCR. METHODS:-acting elements in MAPK10 on miR-4516-mediated modulation and cell migration process. RESULTS:rescued the effect of miR-4516 on the migration of human neural cells. CONCLUSION/CONCLUSIONS:- and posttranscriptional modulation for HSCR pathogenesis.
PMID: 32066630
ISSN: 1468-6244
CID: 4313082
The gastrointestinal development ‘parts list’: transcript profiling of embryonic gut development in wildtype and Ret-deficient mice [PrePrint]
ORIGINAL:0014922
ISSN: 2692-8205
CID: 4772442
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2019:116(52):26697-708.DOI: 10.1073/pnas.1908756116
Gene- and tissue-level interactions in normal gastrointestinal development and Hirschsprung disease
The development of the gut from endodermal tissue to an organ with multiple distinct structures and functions occurs over a prolonged time during embryonic days E10.5-E14.5 in the mouse. During this process, one major event is innervation of the gut by enteric neural crest cells (ENCCs) to establish the enteric nervous system (ENS). To understand the molecular processes underpinning gut and ENS development, we generated RNA-sequencing profiles from wild-type mouse guts at E10.5, E12.5, and E14.5 from both sexes. We also generated these profiles from homozygous Ret null embryos, a model for Hirschsprung disease (HSCR), in which the ENS is absent. These data reveal 4 major features: 1) between E10.5 and E14.5 the developmental genetic programs change from expression of major transcription factors and its modifiers to genes controlling tissue (epithelium, muscle, endothelium) specialization; 2) the major effect of Ret is not only on ENCC differentiation to enteric neurons but also on the enteric mesenchyme and epithelium; 3) a muscle genetic program exerts significant effects on ENS development; and 4) sex differences in gut development profiles are minor. The genetic programs identified, and their changes across development, suggest that both cell autonomous and nonautonomous factors, and interactions between the different developing gut tissues, are important for normal ENS development and its disorders.
PMID: 31818953
ISSN: 1091-6490
CID: 4238762
Sequence characterization of RET in 117 Chinese Hirschsprung disease families identifies a large burden of de novo and parental mosaic mutations
BACKGROUND:Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by the absence of enteric ganglia in the distal part of the gut. RET is the major causative gene and contains > 80% of all known disease-causing mutations. RESULTS:To determine the incidence of RET pathogenic variants, be they Mendelian inherited, mosaic in parents or true de novo variants (DNVs) in 117 Chinese families, we used high-coverage NGS and droplet digital polymerase chain reaction (ddPCR) to identify 15 (12.8%) unique RET coding variants (7 are novel); one was inherited from a heterozygous unaffected mother, 11 were DNVs (73.3%), and 3 full heterozygotes were inherited from parental mosaicism (2 paternal, 1 maternal): two clinically unaffected parents were identified by NGS and confirmed by ddPCR, with mutant allele frequency (13-27%) that was the highest in hair, lowest in urine and similar in blood and saliva. An extremely low-level paternal mosaicism (0.03%) was detected by ddPCR in blood. Six positive-controls were examined to compare the mosaicism detection limit and sensitivity of NGS, amplicon-based deep sequencing and ddPCR. CONCLUSION/CONCLUSIONS:Our findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.
PMID: 31666091
ISSN: 1750-1172
CID: 4163352
A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease
Disruptions in gene regulatory networks (GRNs), driven by multiple deleterious variants, potentially underlie complex traits and diseases. Hirschsprung disease (HSCR), a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and 7 chromosomal loci, with RET and EDNRB as its major genes. We previously demonstrated that RET transcription in the ENS is controlled by an extensive GRN involving the transcription factors (TF) RARB, GATA2 and SOX10 and other HSCR genes. We now demonstrate, using human and mouse cellular and animal models, that EDNRB is transcriptionally regulated in the ENS by GATA2, SOX10 and NKX2.5 TFs. Significantly, RET and EDNRB expression is regulated by their shared use of GATA2 and SOX10 and, in turn, these TFs are controlled by EDNRB and RET in a dose-dependent manner. This study expands the ENS development GRN to include both RET and EDNRB, uncovers the mechanistic basis for RET-EDNRB epistasis and emphasizes how functionally different genes associated with a complex disorder can be united through a common GRN.
PMID: 31313802
ISSN: 1460-2083
CID: 3977902
Journal of pediatric gastroenterology & nutrition. JPGN. 2019:69(3):299-305.DOI: 10.1097/MPG.0000000000002392
High Levels of Interest in Reproductive Genetic Information in Parents of Children and Adults with Hirschsprung Disease
OBJECTIVES/OBJECTIVE:Families affected by Hirschsprung disease (HSCR) have opportunities to learn recurrence risks to their children from statistical genetic and empiric studies and, in some cases, prenatal genetic testing or preimplantation genetic diagnosis (PGD). This study aimed to assess interest in reproductive genetic information for HSCR and factors that predict this interest in two groups with elevated risk of having a child with HSCR. METHODS:Adult HSCR patients and parents of children with HSCR were surveyed about their interest in learning reproductive genetic information regarding HSCR through genetic counseling, prenatal testing, and PGD. Covariates assessed in this cross-sectional study included quality of life, illness perceptions, depressive symptoms, and adaptation to the condition. Bivariate analyses assessed differences between affected adults and parents. Logistic modeling was used to identify predictors of interest in reproductive genetic information. RESULTS:Study participants (n = 368) reported high interest in reproductive genetic information through genetic counseling (yes = 60%/unsure = 16%), prenatal testing (yes = 59%/unsure = 16%), and PGD (yes = 43%/unsure = 18%). Illness perceptions differed between affected adults and parents, but perceived severity of HSCR was high among all participants (μ = 3.42, SD = 0.67, 4 point scale). Interest in reproductive information was associated with being an affected adult, not having a family history of HSCR, negative emotional representations, and adaptation to the condition. CONCLUSIONS:Findings from this study support a desire among the surveyed HSCR patient groups to attend genetic counseling and be offered testing when available. Exploration of perceptions and experiences with the condition should be incorporated into the counseling to insure informed preference-based decision making.
PMID: 31107799
ISSN: 1536-4801
CID: 3978432
Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits
Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
PMCID:6323610
PMID: 30595373
ISSN: 1537-6605
CID: 3975012
Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31
High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.
PMCID:6336803
PMID: 30262922
ISSN: 1476-5438
CID: 3975192
