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1.  Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari Type I Malformation 
Annals of human genetics  2013;78(1):1-12.
Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease-relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on chromosomes 1 (LOD=3.07, p=3×10−3) and 22 (LOD=3.45, p=6×10−5) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.
PMCID: PMC4041368  PMID: 24359474
Posterior cranial fossa; Chiari Type I Malformation; Endophenotypes; Heritability; Ordered subset analysis
2.  Genetic Association Analyses of Nitric Oxide Synthase Genes and Neural Tube Defects Vary by Phenotype 
Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes.
PMCID: PMC4169175  PMID: 24323870
NOS1; NOS2; NOS3; MTHFR; neural tube defect; NTD; anencephaly; spina bifida
3.  Genetic variants in SLC9A9 are associated with measures of Attention-deficit/hyperactivity disorder symptoms in families 
Psychiatric genetics  2010;20(2):73-81.
A family was previously identified that cosegregates a pericentric inversion, inv(3)(p14 : q21), with an early-onset developmental condition, characterized by impulsive behavior and intellectual deficit. The inversion breakpoints lie within DOCK3 and SLC9A9 at the p-arm and q-arm, respectively. Based on this report, these genes were selected to be evaluated in a family-based attention-deficit/hyperactivity disorder (AD/HD) association study.
Conners’ Parent (CPRS) and Teacher (CTRS) Rating Scales of AD/HD symptoms and Conners’ Continuous Performance Test (CPT) measures were collected and a minimal number of tagging singlenucleotide polymorphisms (SNPs) in each gene were selected for analysis. Analyses were performed on families who met research criteria for AD/HD. Using the program, QTDT, each tagging SNP was tested for association with T-scores from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) subscales according to the CTRS and CPRS, and five CPT measures.
After adjusting for multiple testing, a SNP in the 3′ UTR of SLC9A9, rs1046706, remained significantly associated (false discovery rate, q value < 0.05) with scores on the DSM-IV hyperactive-impulsive and total symptom subscales according to the CTRS and errors of commission on the CPT. In addition, an intronic SLC9A9 SNP, rs2360867, remained significantly associated with errors of commission.
Our results suggest that SLC9A9 may be related to hyperactive-impulsive symptoms in AD/HD and the disruption of SLC9A9 may be responsible for the behavioral phenotype observed in the inversion family. The association with SLC9A9 is particularly interesting as it was recently implicated in a genome-wide association study for AD/HD. Further investigation of the role of SLC9A9 in AD/HD and other behavioral disorders is warranted.
PMCID: PMC3085270  PMID: 20032819
attention-deficit/hyperactivity disorder; Conners’ Continuous Performance Test; Conners’ Parent Rating Scale; Conners’ Teacher Rating Scale; genetics; psychiatry; single-nucleotide polymorphism
4.  Missing Genetic Risk in Neural Tube Defects: Can Exome Sequencing Yield an Insight? 
Neural tube defects (NTD) have a strong genetic component, with up to 70% of variance in human prevalence determined by heritable factors. Although the identification of causal DNA variants by sequencing candidate genes from functionally relevant pathways and model organisms has provided some success, alternative approaches are demanded.
Next generation sequencing platforms are facilitating the production of massive amounts of sequencing data, primarily from the protein coding regions of the genome, at a faster rate and cheaper cost than has previously been possible. These platforms are permitting the identification of variants (de novo, rare, and common) that are drivers of NYTD etiology, and the cost of the approach allows for the screening of increased numbers of affected and unaffected individuals from NTD families and in simplex cases.
The next generation sequencing platforms represent a powerful tool in the armory of the genetics researcher to identify the causal genetic basis of NTDs.
PMCID: PMC4169137  PMID: 25044326
next generation exome sequencing; de novo; rare and common variation; compound heterozygosity
5.  Folate Metabolism Genes, Dietary Folate and Response to Antidepressant Medications in Late-Life Depression 
The primary aims of this study were to 1) determine whether folate metabolism genetic polymorphisms predict age of onset and occurrence of late life depression and 2) determine whether folate metabolism genetic polymorphisms predict response to antidepressant medications in late-life depression.
This study used the Conte Center for the Neuroscience of Depression, and the Neurocognitive Outcomes of Depression in the Elderly Study database which includes individuals age ≥ 60. The folate nutrition assessment was determined by the Block Food Frequency Questionnaire. Genotype was evaluated for 15 single nucleotide polymorphisms (SNPs) from 10 folate metabolism genes. Logistic regression models were used to examine genetic polymorphisms and folate estimates with association with depression age of onset and remission status.
There were 304 Caucasians in the database, 106 of these who were not depressed and 198 who had a diagnosis of depression. There were no significant differences between remitters and nonremitters in age, sex or estimated folate intakes. There were no folate estimates or folate metabolism gene SNPs that significantly predicted age of onset of depression or occurrence of depression. MTRR A66G (rs1801394) was significantly associated with remission status (p=0.0077) such that those with the AA genotype were 3.2 times as likely as those with the GG genotype to be in remission (p=0.0020). MTHFR A1298C (rs1801131) achieved a borderline significance for association with remission status (p=0.0313).
The major finding from this study is that the MTRR A66G genotype predicts response to SSRI antidepressants in late life depression.
PMCID: PMC3779127  PMID: 23280573
antidepressants; depression; late-life depression; depressive disorder/genetics; single nucleotide polymorphisms; folate
6.  Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics 
BMC Medical Genomics  2014;7:39.
Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.
A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.
All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.
Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.
PMCID: PMC4082616  PMID: 24962150
Chiari Type I Malformation; Posterior fossa; Disease subtypes; Whole genome expression; Cranial base morphometrics; Clustering
7.  Association of Variant rs4790904 in Protein Kinase C Alpha with Posttraumatic Stress Disorder in a U.S. Caucasian and African-American Veteran Sample 
Journal of depression & anxiety  2013;2(1):S4-001-.
Posttraumatic stress sisorder (PTSD) is a complex anxiety disorder that can develop after traumatic event exposure. Genetic factors have been associated with PTSD risk. Recently a variant rs4790904 in the protein kinase C alpha (PRKCA) gene has been shown to be associated with PTSD risk. The objective of this study was to replicate this association in a sample of U.S. Afghanistan/Iraq era veterans.
The genotypes of rs4790904 were evaluated in all trauma-exposed veterans. The sample of U.S. veterans included 428 Caucasians and 533 African-Americans. The statistical analysis was conducted independently in the Caucasian and African-American subjects to evaluate the association with PTSD symptom clusters of B symptoms (re-experiencing), C symptoms (avoidance and numbing), D symptoms (hyperarousal), and with current PTSD diagnosis.
The sample was comprised of 428 Caucasians (186 with current PTSD diagnosis, 242 trauma-exposed controls; median age, 35 years; 15% female) and 533 African-Americans (205 with current PTSD diagnosis, 328 trauma-exposed controls; median age, 41 years; 31% female). We observed a significant correlation between rs4790904 and all three PTSD symptom clusters in the Caucasian population, but no significant association with current PTSD diagnosis. However, these significant associations were with the G allele, rather than the A allele, that was previously reported by de Quervain. A significant association of this variant with current PTSD diagnosis (p=0.046) was detected in the African-American veterans.
We confirmed the correlation between rs4790904 and all three PTSD symptom clusters in the Caucasian but not the African-American population. A significant association with a current diagnosis of PTSD was found in the African-American veterans.
PMCID: PMC4021713  PMID: 24839585
Posttraumatic stress disorder; single nucleotide polymorphism (SNP); Variant rs4790904
8.  Hepatic Gene Expression Profiles Differentiate Pre-symptomatic Patients with Mild versus Severe Nonalcoholic Fatty Liver Disease 
Hepatology (Baltimore, Md.)  2013;59(2):471-482.
Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into sub-populations at high versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence, might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, “mild” NAFLD patients (fibrosis stage 0–1, n=40) and high risk, “severe” NAFLD patients (fibrosis stage 3–4, n=32). Findings were validated in a second, independent cohort and confirmed by real time PCR and immunohistochemistry. As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically-indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64 gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20 gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and immunohistochemistry confirmed deregulation of metabolic and regenerative pathways in severe NAFLD, and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer.
By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality.
PMCID: PMC3982589  PMID: 23913408
fibrosis; liver disease; biopsy; humans; microarray
9.  Investigation of Known Genetic Risk Factors for Primary Open Angle Glaucoma in Two Populations of African Ancestry 
Multiple genes have been associated with primary open angle glaucoma (POAG) in Caucasian populations. We now examine the association of these loci in populations of African ancestry, populations at particularly high risk for POAG.
We genotyped DNA samples from two populations: African American (1150 cases and 999 controls) and those from Ghana, West Africa (483 cases and 593 controls). Our analysis included 57 single nucleotide polymorphisms (SNPs) in five loci previously associated with POAG at the genome-wide level, including CDKN2B-AS1, TMCO1, CAV1/CAV2, chromosome 8q22 intergenic region, and SIX1/SIX6. We evaluated association in the full datasets, as well as subgroups with normal pressure glaucoma (NPG, maximum IOP ≤21 mm Hg) and high pressure glaucoma (HPG, IOP >21 mm Hg).
In African Americans, we identified an association of rs10120688 in the CDNK2B-AS1 region with POAG (P = 0.0020). Several other SNPs were nominally associated, but did not survive correction for multiple testing. In the subgroup analyses, significant associations were identified for rs10965245 (P = 0.0005) in the CDKN2B-AS1 region with HPG and rs11849906 in the SIX1/SIX6 region with NPG (P = 0.006). No significant association was identified with any loci in the Ghanaian samples.
POAG genetic susceptibility alleles associated in Caucasians appear to play a greatly reduced role in populations of African ancestry. Thus, the major genetic components of POAG of African origin remain to be identified. This finding underscores the critical need to pursue large-scale genome-wide association studies in this understudied, yet disproportionately affected population.
We examined the association of 57 SNPs in five genomic loci in African American individuals and those from Ghana, West Africa, with POAG overall as well as high- and normal-pressure POAG. We confirmed the association with variants in the CDKN2B-AS1 and SIX6/SIX1 regions in the African Americans.
PMCID: PMC3776712  PMID: 23963167
association; genetics; POAG; African; African American
10.  Gene Expression Profile in Human Trabecular Meshwork From Patients With Primary Open-Angle Glaucoma 
To identify the specific genes in human trabecular meshwork (TM) related to POAG.
Primary open-angle glaucoma TM specimens were obtained from routine trabeculectomy surgery. Nonglaucomatous control TM specimens were dissected from donor eyes using the same approach as a standard trabeculectomy. All cases were screened for myocilin (MYOC) mutations. Total RNA was extracted, labeled, and hybridized to Illumina HumanWG-6 BeadChips. Expression data were normalized and analyzed using the R package limma in Bioconductor. Pathway analyses were performed using DAVID Bioinformatics Resources.
Our study included surgical TM specimens from 15 cases and 13 controls. One case was identified with a heterozygous Q368X MYOC mutation. If TMs were available from both eyes in an individual, the expression data were combined for analysis. The following three comparisons were performed for differential analyses: (1) MYOC POAG case versus 14 non-MYOC POAG cases, (2) MYOC POAG case versus 13 controls, and (3) 14 non-MYOC POAG cases versus 13 controls. Limited by one MYOC case in comparisons 1 and 2, expression changes were reported comparing the fold changes but without P values. Comparison 3 identified 483 genes, including 36 components of TM exosomes. Gene ontology analysis identified several enriched functional clusters, including cell adhesion, extracellular matrix, and secretion.
This is the largest TM expression study of POAG cases and controls performed to date and represents the first report of TM expression in a patient having POAG with a Q368X MYOC mutation. Our data suggest the potential role of endocytic and exosome pathways in the pathogenesis of POAG.
We compared the gene expression of human trabecular meshwork from patients with POAG, including one patient carrying the most commonly reported myocilin mutation (Q368X), and from unaffected postmortem donors. Our data indicate the potential role of endocytic and exosome pathways.
PMCID: PMC3787658  PMID: 24003086
gene expression; myocilin; exosome; trabecular meshwork; PAX6
11.  MYH9 and APOL1 are both associated with sickle cell disease nephropathy 
British journal of haematology  2011;155(3):10.1111/j.1365-2141.2011.08832.x.
Renal failure occurs in 5–18% of sickle cell disease (SCD) patients and is associated with early mortality. At risk SCD patients cannot be identified prior to the appearance of proteinuria and the pathobiology is not well understood. The MYH9 and APOL1 genes have been associated with risk for focal segmental glomerulosclerosis and end-stage renal disease in African Americans.
We genotyped 26 SNPs in MYH9 and 2 SNPs in APOL1 in 521 unrelated adult (18–83 years) SCD patients screened for proteinuria. Using logistic regression, SNPs were evaluated for association with proteinuria.
Eight MYH9 SNPs and one APOL1 SNP were nominally associated with proteinuria. Six SNPs remained significant after multiple testing correction (p < 0.0025), and a risk haplotype was associated with proteinuria (p=0.001). Using multiple regression, association with APOL1 diminished in the presence of MYH9 SNPs. Glomerular filtration rate was negatively correlated with proteinuria (p < 0.0001), and was nominally associated with MYH9 and APOL1 in age-adjusted analyses.
Our data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 is more strongly associated than APOL1. These data also provide the opportunity for early identification of patients at risk and new therapeutics.
PMCID: PMC3885232  PMID: 21910715
sickle cell disease; nephropathy; genetics association; genetic modifier; proteinuria
12.  Adverse Subpopulation Regression for Multivariate Outcomes with High-Dimensional Predictors 
Statistics in medicine  2012;31(29):4102-4113.
Biomedical studies have a common interest in assessing relationships between multiple related health outcomes and high-dimensional predictors. For example, in reproductive epidemiology, one may collect pregnancy outcomes such as length of gestation and birth weight and predictors such as single nucleotide polymorphisms in multiple candidate genes and environmental exposures. In such settings, there is a need for simple yet flexible methods for selecting true predictors of adverse health responses from a high-dimensional set of candidate predictors. To address this problem, one may either consider linear regression models for the continuous outcomes or convert these outcomes into binary indicators of adverse responses using pre-defined cutoffs. The former strategy has the disadvantage of often leading to a poorly fitting model that does not predict risk well, while the latter approach can be very sensitive to the cutoff choice. As a simple yet flexible alternative, we propose a method for adverse subpopulation regression (ASPR), which relies on a two component latent class model, with the dominant component corresponding to (presumed) healthy individuals and the risk of falling in the minority component characterized via a logistic regression. The logistic regression model is designed to accommodate high-dimensional predictors, as occur in studies with a large number of gene by environment interactions, through use of a flexible nonparametric multiple shrinkage approach. The Gibbs sampler is developed for posterior computation. The methods are evaluated using simulation studies and applied to a genetic epidemiology study of pregnancy outcomes.
PMCID: PMC3712761  PMID: 22825854
Bayesian; Genetic epidemiology; Latent class model; Logistic regression; Mixture model; Model averaging; Nonparametric; Variable selection
13.  The Kinetics of Urinary Fumonisin B1 Excretion in Humans Consuming Maize-Based Diets 
Molecular nutrition & food research  2012;56(9):10.1002/mnfr.201200166.
Fumonisins (FB) are mycotoxins found in maize. The purpose of this study was to 1) determine the relationship between FB1, FB2 and FB3 intake and urinary excretion in humans, 2) validate a method to isolate urinary FB on C18-SPE cartridges for international shipment, and 3) test the method using samples from Guatemala. Volunteers (n=10) consumed 206 grams/day of tortillas and biscuits prepared from masa flour and a product containing maize flour. Volunteers estimated their daily urine output and samples were analyzed for FB1, FB2 and FB3 and hydrolyzed FB1. Only FB1 was detected in urine suggesting lower absorption of FB2 and FB3. Excretion was highly variable peaking soon after consumption began and decreasing rapidly after consumption stopped. Within five days after consumption ended FB1 was not detected in urine. In a study with eight volunteers, the average total urinary FB1 was 0.5% of the intake. FB1 was detected in 61% (107/177) of the samples collected in Guatemala. The results support the use of urinary FB1 to assess ongoing exposure in population based studies. However, relating the FB1 concentration in urine to dietary intake of FB by individual subjects will be complicated due to inter-individual variability and the rapidity of clearance.
PMCID: PMC3820424  PMID: 22815244
Fumonisin; Fusarium verticillioides; Urinary fumonisin B1
14.  Generalized Admixture Mapping for Complex Traits 
G3: Genes|Genomes|Genetics  2013;3(7):1165-1175.
Admixture mapping is a popular tool to identify regions of the genome associated with traits in a recently admixed population. Existing methods have been developed primarily for identification of a single locus influencing a dichotomous trait within a case-control study design. We propose a generalized admixture mapping (GLEAM) approach, a flexible and powerful regression method for both quantitative and qualitative traits, which is able to test for association between the trait and local ancestries in multiple loci simultaneously and adjust for covariates. The new method is based on the generalized linear model and uses a quadratic normal moment prior to incorporate admixture prior information. Through simulation, we demonstrate that GLEAM achieves lower type I error rate and higher power than ANCESTRYMAP both for qualitative traits and more significantly for quantitative traits. We applied GLEAM to genome-wide SNP data from the Illumina African American panel derived from a cohort of black women participating in the Healthy Pregnancy, Healthy Baby study and identified a locus on chromosome 2 associated with the averaged maternal mean arterial pressure during 24 to 28 weeks of pregnancy.
PMCID: PMC3704244  PMID: 23665878
generalized linear model; local ancestry; mapping by admixture linkage disequilibrium; quadratic normal moment prior; quantitative traits
15.  Effects of Postnatal Parental Smoking on Parent and Teacher Ratings of ADHD and Oppositional Symptoms 
To assess the effects of postnatal parental smoking on subsequent parent and teacher ratings of DSM-IV attention deficit hyperactivity disorder (ADHD) symptoms and oppositional behaviors in children diagnosed with ADHD and their siblings. Children between 5 and 12 years of age with ADHD and their siblings were included. DSM-IV ADHD symptom subscales (Inattentive and hyperactive-impulsive), and oppositionality subscale scores from Conners’ Rating Scales were predicted on the basis of parental smoking status in the first 7 years after birth using Generalized Estimating Equations controlling for a range of relevant covariates. Postnatal parental smoking was associated with both parent and teacher ratings of ADHD symptoms and oppositional behavior. After controlling for a number of covariates, several of these relationships were still significant. The risk of maternal smoking for the development of ADHD symptoms does not end during pregnancy. Research on the mechanisms underlying the observed associations is needed.
PMCID: PMC3678953  PMID: 19525745
ADHD; smoking; disruptive behavior; nicotine dependence
16.  Clinical, radiological, and genetic similarities between patients with Chiari Type I and Type 0 malformations 
Although Chiari Type I (CM-I) and Type 0 (CM-0) malformations have been previously characterized clinically and radiologically, there have been no studies focusing on the possible genetic link between these disorders. The goal of this study was to identify families in whom CM-0 and CM-I co-occurred and to further assess the similarities between these disorders.
Families were ascertained through a proband with CM-I. Detailed family histories were obtained to identify first-degree relatives diagnosed with CM-0. Several criteria were used to exclude individuals with acquired forms of CM-I and/or syringomyelia. Individuals were excluded with syndromic, traumatic, infectious, or tumor-related syringomyelia, as well as CM-I due to a supratentorial mass, hydrocephalus, history of cervical or cranial surgery unrelated to CM-I, or development of symptoms following placement of a lumbar shunt. Medical records and MR images were used to characterize CM-I and CM-0 individuals clinically and radiologically.
Five families were identified in which the CM-I proband had a first-degree relative with CM-0. Further assessment of affected individuals showed similar clinical and radiological features between CM-0 and CM-I individuals, although CM-I patients in general had more severe symptoms and skull base abnormalities than their CM-0 relatives. Overall, both groups showed improvement in symptoms and/or syrinx size following craniocervical decompression surgery.
There is accumulating evidence suggesting that CM-0 and CM-I may be caused by a common underlying developmental mechanism. The data in this study are consistent with this hypothesis, showing similar clinical and radiological features between CM-0 and CM-I individuals, as well as the occurrence of both disorders within families. Familial clustering of CM-0 and CM-I suggests that these disorders may share an underlying genetic basis, although additional epigenetic and/or environmental factors are likely to play an important role in the development of CM-0 versus CM-I.
PMCID: PMC3678957  PMID: 22462700
Chiari malformation; idiopathic syringomyelia; genetics
17.  Central Nervous System Serotonin and Clustering of Hostility, Psychosocial, Metabolic and Cardiovascular Endophenotypes in Men 
Psychosomatic medicine  2010;72(7):601-607.
To use measures of CSF 5HIAA and MAOA-uVNTR genotype to study the role of central nervous system (CNS) serotonin in clustering of hostility, and other psychosocial, metabolic and cardiovascular endophenotypes.
In 86 healthy men, we evaluated cerebrospinal fluid (CSF) levels of the primary serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) and genotype on a functional promoter polymorphism of the monoamine oxidase A gene (M-uVNTR) for association with 29 variables assessing hostility, other psychosocial, metabolic, neuroendocrine and cardiovascular endophenotypes.
The correlations of 5HIAA with these endophenotypes in men with more active MAOA-uVNTR alleles were significantly different from those with less active alleles for 15 of 29 endophenotypes. MAOA-uVNTR phenotype and CSF 5HIAA interacted to explain 20% and 22% of the variance, respectively, in scores on one factor wherein high scores reflected a less healthy psychosocial profile and a second factor wherein high score reflected increased insulin resistance, BMI, blood pressure and hostility. In men with less active alleles, higher 5HIAA was associated with more favorable profiles of hostility, other psychosocial, metabolic and cardiovascular endophenotypes; in men with more active alleles, higher 5HIAA was associated with less favorable profiles.
These findings indicate that in men indices of CNS serotonin function influence the expression and clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes that have been shown to increase risk of developing cardiovascular disease. The findings are consistent with the hypothesis that increased CNS serotonin is associated with a more favorable psychosocial/metabolic/cardiovascular profile, while decreased CNS serotonin function is associated with a less favorable profile.
PMCID: PMC3631777  PMID: 20595415
central nervous system; serotonin; cardiovascular risk factors; hostility; metabolic syndrome components; MAOA-uVNTR polymorphism
18.  Stratified Whole Genome Linkage Analysis of Chiari Type I Malformation Implicates Known Klippel-Feil Syndrome Genes as Putative Disease Candidates 
PLoS ONE  2013;8(4):e61521.
Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of “CTD-negative” families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3–5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.
PMCID: PMC3631233  PMID: 23620759
19.  Impact of Psychological Stress on the Associations Between Apolipoprotein E Variants and Metabolic Traits: Findings in an American Sample of Caregivers and Controls 
Psychosomatic medicine  2010;72(5):427-433.
To examine the association between apolipoprotein E (APOE) gene variants and waist circumference, fasting plasma glucose, serum insulin, serum high-density lipoprotein cholesterol, and serum triglycerides, all metabolic traits known as cardiovascular disease (CVD) endophenotypes, in a population of stressed individuals and controls. Abdominal obesity, insulin resistance, elevated serum lipid concentration, and APOE polymorphisms have been associated with CVD risk. Current evidence supports the hypothesis that gene-environment interactions modulate serum lipid concentrations.
The association between rs769450, rs405509, rs439401, and metabolic traits were analyzed in a U.S. sample of 126 white caregivers of a relative with Alzheimer's disease or other major dementia and 122 white controls. The associations were analyzed, using multivariate analysis of variance adjusted for age, sex, and medications.
Significant multivariate interactions were found, using both additive (p = .009) and dominant (p = .047) models between rs439401 (C/T) and caregiver stress in relation to a profile of metabolic variables. Univariate analyses found the TT genotype to be associated with more adverse levels of waist circumference (interaction, p = .026), triglycerides (interaction, p = .001) and high-density lipoprotein cholesterol (interaction, p = .001) among caregivers but with a more favorable profile of these endophenotypes among controls. There were no significant associations or interactions involving the other two single nucleotide polymorphisms.
The APOE rs439401 TT genotype is associated with an adverse metabolic profile among chronically stressed individuals compared with individuals not similarly stressed in whom a more favorable profile is expressed. Confirmation of these results in further research would indicate that the TT genotype can be used to identify persons at high risk for CVD when subjected to chronic stress.
PMCID: PMC3625667  PMID: 20467002
apolipoprotein E; obesity; metabolic traits; stress; epidemiology; gene-environment interaction
20.  A Preliminary Analysis of Interactions Between Genotype, Retrospective ADHD Symptoms, and Initial Reactions to Smoking in a Sample of Young Adults 
Nicotine & Tobacco Research  2011;14(2):229-233.
Initial reactions to cigarettes predict later regular smoking. Symptoms of attention deficit hyperactivity disorder (ADHD) have also been shown to increase smoking risk and may moderate the relationship between genotype and smoking. We conducted an exploratory study to assess whether ADHD symptoms interact with genetic variation to predict self-reported initial reactions to smoking.
Participants were a subsample of 1,900 unrelated individuals with genotype data drawn from the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. Linear regression was used to examine relationships among self-reported ADHD symptoms, genotype, and self-reported initial reactions to cigarettes (index scores reflecting pleasant and unpleasant reactions).
Polymorphisms in the DRD2 gene, SLC6A4 gene, and among males, the MAOA gene interacted with retrospective reports of ADHD symptoms in predicting pleasant initial reaction to cigarettes. Polymorphisms in the CYP2A6 gene and, among females, the MAOA gene interacted with retrospective reports of ADHD symptoms in predicting unpleasant initial reaction to cigarettes. No main effect for any of these polymorphisms was observed nor were any interactions with DRD4 and DAT genes.
These findings suggest that genotypes associated with monoamine neurotransmission interact with ADHD symptoms to influence initial reactions to cigarette smoking. Given that an initial pleasant reaction to cigarettes increases risk for lifetime smoking, these results add to a growing body of literature that suggests that ADHD symptoms increase risk for smoking and should be accounted for in genetic studies of smoking.
PMCID: PMC3265740  PMID: 21778150
21.  Exome Analysis of Two Limb-Girdle Muscular Dystrophy Families: Mutations Identified and Challenges Encountered 
PLoS ONE  2012;7(11):e48864.
The molecular diagnosis of muscle disorders is challenging: genetic heterogeneity (>100 causal genes for skeletal and cardiac muscle disease) precludes exhaustive clinical testing, prioritizing sequencing of specific genes is difficult due to the similarity of clinical presentation, and the number of variants returned through exome sequencing can make the identification of the disease-causing variant difficult. We have filtered variants found through exome sequencing by prioritizing variants in genes known to be involved in muscle disease while examining the quality and depth of coverage of those genes. We ascertained two families with autosomal dominant limb-girdle muscular dystrophy of unknown etiology. To identify the causal mutations in these families, we performed exome sequencing on five affected individuals using the Agilent SureSelect Human All Exon 50 Mb kit and the Illumina HiSeq 2000 (2×100 bp). We identified causative mutations in desmin (IVS3+3A>G) and filamin C (p.W2710X), and augmented the phenotype data for individuals with muscular dystrophy due to these mutations. We also discuss challenges encountered due to depth of coverage variability at specific sites and the annotation of a functionally proven splice site variant as an intronic variant.
PMCID: PMC3498247  PMID: 23155419
22.  Maternal Vitamin D Receptor Genetic Variation Contributes to Infant Birthweight among Black Mothers 
Racial disparity in pregnancy outcomes is one of the most striking and poorly understood inequalities in American health. Genetic variability may be an important host factor influencing disparate birth outcomes between non-Hispanic black (NHB) and non-Hispanic white (NHW) women. Race-specific allelic frequencies in the vitamin D receptor (VDR) gene suggest its potential as a gene involved in health disparities. The Healthy Pregnancy, Healthy Baby Study is a prospective cohort of pregnant women aimed at identifying genetic, social, and environmental contributors to disparities in pregnancy outcomes in Durham, NC. VDR haplotype tagging SNPs were genotyped via Taqman assays for 615 women. Analysis of variance was used to examine the association between maternal genotype and infant birthweight. Eight of 38 SNPs examined showed nominal significance among NHB women, with one VDR SNP (rs7975232) surpassing the multiple testing significance threshold. rs7975232, an anonymous polymorphism, is part of a VDR gene haplotype associated with variation in mRNA stability. mRNA stability can affect the amount of protein produced, thus directly affecting vitamin D levels and calcium homeostasis. In contrast to NHBs, there was no association between any VDR SNP and birthweight for NHWs. Genetic factors contributing to disparities in birth outcomes are not expected to be explained entirely by variation in a single gene. Nevertheless, our results suggest that maternal VDR gene polymorphisms do influence birthweight with differential effects accruing across racial groups. Further research identifying the functionality of VDR gene polymorphisms in pregnant women will improve our understanding of the underlying mechanisms influencing birthweight.
PMCID: PMC3100406  PMID: 21548019
Infant birthweight; Vitamin D receptor gene; Racial disparity
23.  Natural Food Folate and Late-Life Depression 
Low folate status has been linked to depression but findings have been inconsistent. The authors sought to examine the association between folate intake and late-life depression. This cross-sectional study included individuals age 60 and over (n=111 depression, n=136 comparison). Depression participants received psychiatric care. Folate and kilocalorie intakes were assessed with a Block 1998 food frequency questionnaire. Naturally occurring food folate was inversely associated with depression after controlling for age, sex, race, education, and total energy (p=0·0047). All other folate variables including total dietary folate and folic acid were non-significant for depression. These findings may indicate that the naturally occurring form of folate is uniquely protective for depression and perhaps brain health. Alternatively, natural folate may be a surrogate for other nutrients or overall dietary quality.
PMCID: PMC3324853  PMID: 21184377
folate; folic acid; older adults; depression; nutrition
24.  Genes implicated in serotonergic and dopaminergic functioning predict BMI categories 
Obesity (Silver Spring, Md.)  2008;16(2):348-355.
This study addressed the hypothesis that variation in genes associated with dopamine function (SLC6A3, DRD2, DRD4), serotonin function (SLC6A4), and regulation of monoamine levels (MAOA) may be predictive of BMI categories (obese and overweight + obese) in young adulthood and of changes in BMI as adolescents transition into young adulthood. Interactions with gender and race/ethnicity were also examined.
Research Methods and Procedures
Participants were a subsample of individuals from The National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. The sample analyzed included a subset of 1584 unrelated individuals with genotype data. Multiple logistic regressions were conducted to evaluate associations between genotypes and obesity (BMI > 29.9) or overweight + obese combined (BMI > 25) with normal weight (BMI = 18.5–24.9) as a referent. Linear regression models were used examine change in BMI from adolescence to young adulthood.
Significant associations were found between SLC6A4 5HTTLPR and categories of BMI, and between MAOA promoter VNTR among males and categories of BMI. Stratified analyses revealed that the association between these two genes and excess BMI was significant for males overall, and for White and Hispanic males specifically. Linear regression models indicated a significant effect of SLC6A4 5HTTLPR on change in BMI from adolescence to young adulthood.
Our findings lend further support to the involvement of genes implicated in dopamine and serotonin regulation on energy balance.
PMCID: PMC2919156  PMID: 18239643
Adolescents; Genetic Epidemiology; Serotonin; Neuro Transmitter
25.  Interactions between genotype and depressive symptoms on obesity 
Behavior genetics  2009;39(3):296-305.
Depression and Genetic variation in serotonin and monoamine transmission have both been associated with Body Mass Index (BMI), but their interaction effects are not well understood. We examined the interaction between depressive symptoms and functional polymorphisms of serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) on categories of BMI.
Participants were from the National Longitudinal Study of Adolescent Health. Multiple logistic regression was used to investigate interactions between candidate genes and depression on risk of obesity (BMI≥30) or overweight + obese combined (BMI≥25).
Males with an MAOA active allele with high depressive symptoms were at decreased risk of obesity (OR, 0.22; 95% CI, 0.06 – 0.78) and overweight + obesity (OR, 0.48; 95% CI, 0.26 – 0.89). No similar effect was observed among females.
These findings highlight that the obesity-depression relationship may vary as a function of gender and genetic polymorphism, and suggest the need for further study.
PMCID: PMC2884968  PMID: 19337825

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