Publications by authors named "Nicole D Dueker"

11 Publications

  • Page 1 of 1

Family History of Eating Disorder and the Broad Autism Phenotype in Autism.

Autism Res 2020 09 5;13(9):1573-1581. Epub 2020 Sep 5.

University of Miami Miller School of Medicine, Miami, FL, USA.

Autism features occur frequently among individuals with eating disorders (ED). This co-occurrence is not well understood but there is speculation that select traits (e.g., rigidity) are common to both autism and ED. To explore the co-occurrence of autistic traits and ED features, we used the Simons Simplex Collection (SSC; N = 2,623 families) to test whether first-degree relatives of individuals with autism with a history of ED features had more autism traits, as measured by the Broad Autism Phenotype Questionnaire (BAP-Q), compared to relatives with no history of ED. The frequency of individuals with ED features was 2.2% (N = 57) among mothers, <1% in siblings, and not present in fathers. We restricted our analyses to mothers. Compared to mothers with no history of ED, those with a history of ED had significantly higher scores on the BAP-Q Total Score and each of the three BAP-Q domains. More importantly, when the BAP-Q was used as a classification tool, we found that when compared to mothers with no history of ED, those with a history of ED were most likely to fall into the clinically significant range on the BAP-Q Rigid domain. Our results suggest that a history of ED features among mothers of individuals with autism is associated with the presence of autistic traits. This extends previous work showing a relationship between autism and ED and expands the range of neuropsychiatric traits that have relevance to the BAP among family members of individuals with autism. LAY SUMMARY: Using information from the Simons Simplex Collection we tested whether mothers of individuals with autism with a history of eating disorder had more autism traits (i.e., similar to those in autism but milder) compared to mothers with no history of eating disorder. The most striking difference between the groups was the presence of rigidity in mothers with a history of eating disorder. This extends previous work showing a relationship between autism and eating disorders and suggests the utility of studying eating disorders in future family studies of autism. Autism Res 2020, 13: 1573-1581. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/aur.2378DOI Listing
September 2020

Extreme Phenotype Approach Suggests Taste Transduction Pathway for Carotid Plaque in a Multi-Ethnic Cohort.

Stroke 2020 09 19;51(9):2761-2769. Epub 2020 Aug 19.

Department of Neurology (H.G., C.D., D.D.-M., R.L.S., T.R.), University of Miami, FL.

Background And Purpose: Carotid plaque is a heritable trait and a strong predictor of vascular events. Several loci have been identified for carotid plaque, however, studies in minority populations are lacking. Within a multi-ethnic cohort, we have identified individuals with extreme total carotid plaque area (TCPA), that is, higher or lower TCPA than expected based on traditional vascular risk factors (age, sex, smoking, diabetes mellitus, hypertension, etc). We hypothesized that these individuals are enriched with genetic variants accounting for the plaque burden that cannot be explained by traditional vascular risk factors. Herein, we sought to identify the genetic basis for TCPA using the multi-ethnic cohort.

Methods: Three hundred forty participants (170 from each extreme group) from 3 race/ethnic groups (53% Hispanic, 29% non-Hispanic Black, and 18% non-Hispanic White) were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array and imputed using 1000Genome data. SNP-based analyses using logistic regression and gene-based analyses using VEGAS2 were performed within each race/ethnic group and then meta-analyzed. Genes with <0.001 were included in an overrepresentation enrichment pathway analysis using WebGestalt. Promising findings were tested for association with ischemic stroke using the MEGASTROKE Consortium data set.

Results: No SNP or gene reached genome-wide significance. In the pathway analysis, GO:0050913 (sensory perception of bitter taste) gene set was significantly enriched (=4.5×10, false discovery rate=0.04), which was confirmed in MEGASTROKE (=0.01). Within the GO:0050913 gene set, 3 genes were associated with extreme TCPA in our study (<0.001): , , and . In , rs1376251 is the top SNP and has been associated with myocardial infarction by others. In , a SNP with high regulatory potential (rs3818527, RegulomeScore=1f), and itself were among the top SNP-based and gene-based results and showed consistent evidence for association in all ethnic groups (<0.05).

Conclusions: Extreme TCPA analysis identified new candidate genes for carotid plaque in understudied populations.
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http://dx.doi.org/10.1161/STROKEAHA.120.028979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483772PMC
September 2020

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

Stroke 2020 07 10;51(7):2111-2121. Epub 2020 Jun 10.

Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

Background And Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.

Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.

Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (), 10q23.1 (), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 () and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.

Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
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http://dx.doi.org/10.1161/STROKEAHA.119.027544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365038PMC
July 2020

Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.

Nat Commun 2019 01 3;10(1):29. Epub 2019 Jan 3.

Department of Pathology, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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http://dx.doi.org/10.1038/s41467-018-07867-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318312PMC
January 2019

Sequencing of Linkage Region on Chromosome 12p11 Identifies as a Candidate Gene for Left Ventricular Mass in Dominican Families.

G3 (Bethesda) 2018 02 2;8(2):659-668. Epub 2018 Feb 2.

Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Florida 33136

Increased left ventricular mass (LVM) is an intermediate phenotype for cardiovascular disease (CVD) and a predictor of stroke. Using families from the Dominican Republic, we have previously shown LVM to be heritable and found evidence for linkage to chromosome 12p11. Our current study aimed to further characterize the QTL by sequencing the 1 LOD unit down region in 10 families from the Dominican Republic with evidence for linkage to LVM. Within this region, we tested 5477 common variants [CVs; minor allele frequency (MAF) ≥5%] using the Quantitative Transmission-Disequilibrium Test (QTDT). Gene-based analyses were performed to test rare variants (RVs; MAF < 5%) in 181 genes using the family-based sequence kernel association test. A sample of 618 unrelated Dominicans from the Northern Manhattan Study (NOMAS) and 12 Dominican families with Exome Array data were used for replication analyses. The most strongly associated CV with evidence for replication was rs1046116 (Discovery families = 9.0 × 10; NOMAS = 0.03; replication families = 0.46), a missense variant in In nonsynonymous RV analyses, was one of the most strongly associated genes ( = 0.05) with suggestive evidence for replication in NOMAS ( = 0.05). encodes the plakophilin 2 protein and is a desmosomal gene implicated in arrythmogenic right ventricular cardiomyopathy and recently in arrhythmogenic left ventricular cardiomyopathy, which makes 2 an excellent candidate gene for LVM. In conclusion, sequencing of our previously reported QTL identified common and rare variants within to be associated with LVM. Future studies are necessary to elucidate the role these variants play in influencing LVM.
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http://dx.doi.org/10.1534/g3.117.300358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919734PMC
February 2018

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.

J Clin Invest 2017 May 10;127(5):1798-1812. Epub 2017 Apr 10.

Background: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

Methods: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

Results: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

Conclusion: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

Funding: For detailed information per study, see Acknowledgments.
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http://dx.doi.org/10.1172/JCI84840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409098PMC
May 2017

Sickle Cell Trait and Renal Function in Hispanics in the United States: The Northern Manhattan Study.

Ethn Dis 2017 01 19;27(1):11-14. Epub 2017 Jan 19.

John P. Hussman Institute for Human Genomics, University of Miami; Dr. John T. Macdonald Department of Human Genetics, University of Miami.

Sickle cell anemia (SCA) is a common hematological disorder among individuals of African descent in the United States; the disorder results in the production of abnormal hemoglobin. It is caused by homozygosity for a genetic mutation in HBB; rs334. While the presence of a single mutation (sickle cell trait, SCT) has long been considered a benign trait, recent research suggests that SCT is associated with renal dysfunction, including a decrease in estimated glomerular filtration rate (eGFR) and increased risk of chronic kidney disease (CKD) in African Americans. It is currently unknown whether similar associations are observed in Hispanics. Therefore, our study aimed to determine if SCT is associated with mean eGFR and CKD in a sample of 340 Dominican Hispanics from the Northern Manhattan Study. Using regression analyses, we tested rs334 for association with eGFR and CKD, adjusting for age and sex. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and CKD was defined as eGFR < 60 mL/min/1.73 m. Within our sample, there were 16 individuals with SCT (SCT carriers). We found that SCT carriers had a mean eGFR that was 12.12 mL/min/1.73m lower than non-carriers (P=.002). Additionally, SCT carriers had 2.72 times higher odds of CKD compared with non-carriers (P=.09). Taken together, these novel results show that Hispanics with SCT, as found among African Americans with SCT, may also be at increased risk for kidney disease.
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http://dx.doi.org/10.18865/ed.27.1.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245602PMC
January 2017

Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families.

PLoS One 2016 9;11(12):e0167202. Epub 2016 Dec 9.

Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, United States of America.

Cardiovascular disorders including ischemic stroke (IS) and myocardial infarction (MI) are heritable; however, few replicated loci have been identified. One strategy to identify loci influencing these complex disorders is to study subclinical phenotypes, such as carotid bifurcation intima-media thickness (bIMT). We have previously shown bIMT to be heritable and found evidence for linkage and association with common variants on chromosome 7p for bIMT. In this study, we aimed to characterize contributions of rare variants (RVs) in 7p to bIMT. To achieve this aim, we sequenced the 1 LOD unit down region on 7p in nine extended families from the Dominican Republic (DR) with strong evidence for linkage to bIMT. We then performed the family-based sequence kernel association test (famSKAT) on genes within the 7p region. Analyses were restricted to single nucleotide variants (SNVs) with population based minor allele frequency (MAF) <5%. We first analyzed all exonic RVs and then the subset of only non-synonymous RVs. There were 68 genes in our analyses. Nucleotide-binding oligomerization domain (NOD1) was the most significantly associated gene when analyzing exonic RVs (famSKAT p = 9.2x10-4; number of SNVs = 14). We achieved suggestive replication of NOD1 in an independent sample of twelve extended families from the DR (p = 0.055). Our study provides suggestive statistical evidence for a role of rare variants in NOD1 in bIMT. Studies in mice have shown Nod1 to play a role in heart function and atherosclerosis, providing biologic plausibility for a role in bIMT thus making NOD1 an excellent bIMT candidate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167202PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147882PMC
July 2017

Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants.

Mol Autism 2015 7;6:43. Epub 2015 Jul 7.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136 USA ; Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136 USA.

Background: Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD.

Methods: We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive annotation to identify single variants which could confer ASD risk and also gene-based association analysis to identify sets of rare variants associated with ASD.

Results: We identified a significant over-representation of rare loss-of-function variants in genes previously associated with ASD, including a de novo premature stop variant in the well-established ASD candidate gene RBFOX1. Furthermore, ASD cases were more likely to have two damaging missense variants in candidate genes than controls. Finally, gene-based rare variant association implicates genes functioning in excitatory neurotransmission and neurite outgrowth and guidance pathways including CACNAD2, KCNH7, and NRXN1.

Conclusions: We find suggestive evidence that rare variants in synaptic genes are associated with ASD and that loss-of-function mutations in ASD candidate genes are a major risk factor, and we implicate damaging mutations in glutamate signaling receptors and neuronal adhesion and guidance molecules. Furthermore, the role of de novo mutations in ASD remains to be fully investigated as we identified the first reported protein-truncating variant in RBFOX1 in ASD. Overall, this work, combined with others in the field, suggests a convergence of genes and molecular pathways underlying ASD etiology.
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http://dx.doi.org/10.1186/s13229-015-0034-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504419PMC
July 2015

Analysis of genetic linkage data for Mendelian traits.

Curr Protoc Hum Genet 2014 Oct 1;83:1.4.1-31. Epub 2014 Oct 1.

University of Miami Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, Florida.

This unit describes linkage analysis, an invaluable tool in mapping human disease genes. Linkage analysis is one of several methods used to map genes. Specifically, in linkage analysis, cosegregation of two or more genes (traits) is examined in a family unit to determine if they segregate independently of each other according to Mendel's laws or if they do not segregate independently because of their close physical proximity. The procedures outlined in this unit are not always straightforward, and a number of caveats are presented in the commentary regarding possible complications and confounding factors that may arise. Specific examples are given, but it is not possible to cover all possible scenarios or variables. The intention is to enable the reader to master basic principles used in the linkage approach, and thus be in a position to undertake, with proper consultation, a linkage-analysis study. This unit deals specifically with lod score analysis in Mendelian disorders.
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http://dx.doi.org/10.1002/0471142905.hg0104s83DOI Listing
October 2014

Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.

Mol Autism 2014 Jan 10;5(1). Epub 2014 Jan 10.

John P, Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, 1501 NW 10th Avenue, BRB-314 (M860), Miami, FL, USA.

Background: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered.

Methods: To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized.

Results: We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 × 10-5).

Conclusions: By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases.
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http://dx.doi.org/10.1186/2040-2392-5-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896704PMC
January 2014