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1.  Polygenic Transmission and Complex Neuro developmental Network for Attention Deficit Hyperactivity Disorder: Genome-Wide Association Study of Both Common and Rare Variants 
Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case–control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein–Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology.
PMCID: PMC4321789  PMID: 23728934
ADHD; GWAS; pathway; neurodevelopment
2.  The FMR1 Gene and Fragile X-Associated Tremor/Ataxia Syndrome 
The CGG-repeat present in the 5′UTR of the FMR1 gene is unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In fragile X patients, a repeat length exceeding 200 CGGs (full mutation: FM) generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The gene product FMRP is involved in regulation of transport and translation of certain mRNA in the dendrite, thereby affecting synaptic plasticity. This is central to learning and memory processes. The absence of FMRP seen in FM is the cause of the mental retardation seen in fragile X patients. The premutation (PM) is defined as 55–200 CGGs. Female PM carriers are at risk of developing primary ovarian insufficiency. Recently it was discovered that elderly PM carriers might develop a progressive neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome. Although arising from the mutations in the same gene, distinct mechanisms lead to fragile X syndrome (absence of FMRP) and FXTAS (toxic RNA gain of function). The pathogenic mechanisms thought to underlie these disorders are discussed, with a specific emphasis on FXTAS. This review gives insight on the implications of all possible repeat length categories seen in fragile X families.
PMCID: PMC4320942  PMID: 19105204
FMR1; FMRP; fragile X; FXTAS; CGG repeat instability; RNA gain-of-function
3.  Accuracy of Phenotyping of Autistic Children Based on Internet Implemented Parent Report 
While strong familial evidence supports a substantial genetic contribution to the etiology of autism spectrum disorders (ASD), specific genetic abnormalities have been identified in only a small minority of all cases. In order to comprehensively delineate the genetic components of autism including the identification of rare and common variants, overall sample sizes an order of magnitude larger than those currently under study are critically needed. This will require rapid and scalable subject assessment paradigms that obviate clinic-based time-intensive behavioral phenotyping, which is a rate-limiting step. Here, we test the accuracy of a web-based approach to autism phenotyping implemented within the Interactive Autism Network (IAN). Families who were registered with the IAN and resided near one of the three study sites were eligible for the study. One hundred seven children ascertained from this pool who were verbal, age 4–17 years, and had Social Communication Questionnaire (SCQ) scores ≥12 (a profile that characterizes a majority of ASD -affected children in IAN) underwent a clinical confirmation battery. One hundred five of the 107 children were ASD positive (98%) by clinician’s best estimate. One hundred four of these individuals (99%) were ASD positive by developmental history using the Autism Diagnostic Interview-Revised (ADI-R) and 97 (93%) were positive for ASD by developmental history and direct observational assessment (Autism Diagnostic Observational Schedule or expert clinician observation). These data support the reliability and feasibility of the IAN-implemented parent-report paradigms for the ascertainment of clinical ASD for large-scale genetic research.
PMCID: PMC4311721  PMID: 20552678
autism; ASD; sample size; genetic studies; rapid phenotyping paradigm
4.  Genome-Wide Significant Localization for Working and Spatial Memory: Identifying Genes for Psychosis Using Models of Cognition 
It is well established that risk for developing psychosis is largely mediated by the influence of genes, but identifying precisely which genes underlie that risk has been problematic. Focusing on endophenotypes, rather than illness risk, is one solution to this problem. Impaired cognition is a well-established endophenotype of psychosis. Here we aimed to characterize the genetic architecture of cognition using phenotypically detailed models as opposed to relying on general IQ or individual neuropsychological measures. In so doing we hoped to identify genes that mediate cognitive ability which might also contribute to psychosis risk. Hierarchical factor models of genetically clustered cognitive traits were subjected to linkage analysis followed by QTL region-specific association analyses in a sample of 1,269 Mexican American individuals from extended pedigrees. We identified four genome wide significant QTLs, two for working and two for spatial memory, and a number of plausible and interesting candidate genes. The creation of detailed models of cognition seemingly enhanced the power to detect genetic effects on cognition and provided a number of possible candidate genes for psychosis.
PMCID: PMC4106137  PMID: 24243780
schizophrenia; genetics; cognition; GWAS; linkage
5.  Epigenetic studies in Alzheimer’s disease: current findings, caveats and considerations for future studies 
Alzheimer’s disease (AD) is a sporadic, chronic neurodegenerative disease, usually occurring late in life. The last decade has witnessed tremendous advances in our understanding about the genetic basis of AD, but a large amount of the variance in disease risk remains to be explained. Epigenetic mechanisms, which developmentally regulate gene expression via modifications to DNA, histone proteins and chromatin, have been hypothesised to play a role in other complex neurobiological diseases, and studies to identify genome-wide epigenetic changes in AD are currently under way. However, the simple brute-force approach that has been successfully employed in genome-wide association studies is unlikely to be successful in epigenome-wide association studies of neurodegeneration. A more academic approach to understanding the role of epigenetic variation in AD is required, with careful consideration of study design, methodological approaches, tissue-specificity, and causal inference. In this article we review the empirical literature supporting a role for epigenetic processes in AD, and discuss important considerations and future directions for this new and emerging field of research.
PMCID: PMC3947441  PMID: 24038819
Dementia; DNA methylation; brain; neurodegeneration; genetics
6.  Ordered Subsets Linkage Analysis of Antisocial Behavior in Substance Use Disorder Among Participants in the Collaborative Study on the Genetics of Alcoholism 
Heterogeneity in complex diseases such as Substance Use Disorder (SUD) reduces the power to detect linkage and makes replication of findings in other populations unlikely. It is therefore critical to refine the phenotype and use methods that account for genetic heterogeneity between families. SUD was operationalized as diagnosis of abuse or dependence to alcohol and/or any one of five illicit substances. Whole-genome linkage analysis of 241 extended pedigree families from the Collaborative Study on the Genetics of Alcoholism was performed in Merlin using an affected sibship design. An Ordered Subsets Analysis (OSA) using FLOSS sought to increase the homogeneity of the sample by ranking families by their density of childhood and adult antisocial behaviors, producing new maximum Nonparametric Lod (NPL) scores on each chromosome for each subset of families. Prior to OSA, modest evidence for linkage was found on chromosomes 8 and 17. Although changes in NPL scores were not statistically significant, OSA revealed possible evidence of linkages on chromosome 7, near markers D7S1795 and D7S821. NPL scores >3.0 were also observed on chromosomes 2, 3, 5, 9, and 14. However, the number of families used in these latter subsets for linkage may be too small to be meaningful. Results provide some evidence for the ability of OSA to reduce genetic heterogeneity, and add further support to chromosome 7 as a possible location to search for genes related to various SUD related processes. Nonetheless, replication of these results in other samples is essential.
PMCID: PMC4248599  PMID: 18496835
alcohol; antisocial behavior; linkage; ordered subsets analysis; COGA
7.  Genetic Predictors of Risk and Resilience in Psychiatric Disorders: A Cross-Disorder Genome-wide Association Study of Functional Impairment in Major Depressive Disorder, Bipolar Disorder, and Schizophrenia 
Functional impairment is one of the most enduring, intractable consequences of psychiatric disorders and is both familial and heritable. Previous studies have suggested that variation in functional impairment can be independent of symptom severity. Here we report the first genome-wide association study (GWAS) of functional impairment in the context of major mental illness. Participants of European-American descent (N=2,246) were included from three large treatment studies of bipolar disorder (STEP-BD) (N=765), major depressive disorder (STAR*D) (N=1091), and schizophrenia (CATIE) (N=390). At study entry, participants completed the SF-12, a widely-used measure of health-related quality of life. We performed a GWAS and pathway analysis of the mental and physical components of health-related quality of life across diagnosis (~1.6 million single nucleotide polymorphisms), adjusting for psychiatric symptom severity. Psychiatric symptom severity was a significant predictor of functional impairment, but it accounted for less than one-third of the variance across disorders. After controlling for diagnostic category and symptom severity, the strongest evidence of genetic association was between variants in ADAMTS16 and physical functioning (p=5.87 × 10−8). Pathway analysis did not indicate significant enrichment after correction for gene clustering and multiple testing. This study illustrates a phenotypic framework for examining genetic contributions to functional impairment across psychiatric disorders.
PMCID: PMC4019336  PMID: 24039173
SF-12; health-related quality of life; disability; genetics; ADAMTS16
8.  A recessive genetic model and runs of homozygosity in major depressive disorder 
Genome-wide association studies (GWASs) of major depressive disorder (MDD) have yet to identify variants that surpass the threshold for genome-wide significance. A recent study reported that runs of homozygosity (ROH) are associated with schizophrenia, reflecting a novel genetic risk factor resulting from increased parental relatedness and recessive genetic effects. Here we undertake an analysis of ROH for MDD using the 9,238 MDD cases and 9,521 controls reported in a recent mega-analysis of 9 GWAS. Since evidence for association with ROH could reflect a recessive mode of action at loci, we also conducted a genome-wide association analyses under a recessive model.
The genome-wide association analysis using a recessive model found no significant associations. Our analysis of ROH suggested that there was significant heterogeneity of effect across studies in effect (p=0.001), and it was associated with genotyping platform and country of origin. The results of the ROH analysis show that differences across studies can lead to conflicting systematic genome-wide differences between cases and controls that are unaccounted for by traditional covariates. They highlight the sensitivity of the ROH method to spurious associations, and the need to carefully control for potential confounds in such analyses. We found no strong evidence for a recessive model underlying MDD.
PMCID: PMC4234115  PMID: 24482242
9.  Allelic Association, DNA Resequencing and Copy Number Variation at the Metabotropic Glutamate Receptor GRM7 Gene Locus in Bipolar Disorder 
Genetic markers at the GRM7 gene have shown allelic association with bipolar disorder (BP) in several case–control samples including our own sample. In this report, we present results of resequencing the GRM7 gene in 32 bipolar samples and 32 random controls selected from 553 bipolar cases and 547 control samples (UCL1). Novel and potential etiological base pair changes discovered by resequencing were genotyped in the entire UCL case–control sample. We also report on the association between GRM7 and BP in a second sample of 593 patients and 642 controls (UCL2). The three most significantly associated SNPs in the original UCL1 BP GWAS sample were genotyped in the UCL2 sample, of which none were associated. After combining the genotype data for the two samples only two (rs1508724 and rs6769814) of the original three SNP markers remained significantly associated with BP. DNA sequencing revealed mutations in three cases which were absent in control subjects. A 3′-UTR SNP rs56173829 was found to be significantly associated with BP in the whole UCL sample (P = 0.035; OR = 0.482), the rare allele being less common in cases compared to controls. Bioinformatic analyses predicted a change in the centroid secondary structure of RNA and alterations in the miRNA binding sites for the mutated base of rs56173829. We also validated two deletions and a duplication within GRM7 using quantitative-PCR which provides further support for the pre-existing evidence that copy number variants at GRM7 may have a role in the etiology of BP. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Published by Wiley Periodicals, Inc.
PMCID: PMC4231221  PMID: 24804643
genetic; case–control; allelic association study; 3′-UTR; CNV
10.  Blood-Based Gene-Expression Biomarkers of Post-Traumatic Stress Disorder among Deployed Marines: A Pilot Study 
The etiology of post-traumatic stress disorder (PTSD) likely involves the interaction of numerous genes and environmental factors. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain tissues. In that context, this pilot study sought to test the following hypotheses: 1) post-trauma expression levels of a gene subset in peripheral blood would differ between Marines with and without PTSD; 2) a diagnostic biomarker panel of PTSD among high-risk individuals could be developed based on gene expression in readily assessable peripheral blood cells; and 3) a diagnostic panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels in peripheral blood samples from 50 U.S. Marines (25 PTSD cases and 25 non-PTSD comparison subjects) were determined by microarray following their return from deployment to war-zones in Iraq or Afghanistan. The original sample was carved into training and test subsets for construction of support vector machine classifiers. The panel of peripheral blood biomarkers achieved 80% prediction accuracy in the test subset based on the expression of just two full-length transcripts (GSTM1 and GSTM2). A biomarker panel based on 20 exons attained an improved 90% accuracy in the test subset. Though further refinement and replication of these biomarker profiles are required, these preliminary results provide proof-of-principle for the diagnostic utility of blood-based mRNA-expression in PTSD among trauma-exposed individuals.
PMCID: PMC4199086  PMID: 23650250
alternative splicing; mRNA; peripheral blood mononuclear cells; gene expression; microarray; transcriptome; trauma; diagnosis; biomarker; antioxidant; oxidative stress
12.  Association of catechol-O-methyltransferase gene polymorphisms with schizophrenia and negative symptoms in a Chinese population 
The gene encoding Catechol O-methyltransferase (COMT), a dopamine catabolic enzyme, has been associated inconsistently with schizophrenia in spite of consistent evidence for dopaminergic dysfunction in the prefrontal cortex (PFC) of schizophrenia. Since one contribution to this inconsistency might be genetic heterogeneity, this study investigated whether the COMT gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese schizophrenic patients. We analyzed two polymorphisms (rs740603 and rs4818) of the COMT gene in a case–control study of 604 Han Chinese (284 patients and 320 controls). The patients’ psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups. Quantitative trait analysis by the UNPHASED program showed that the rs740603 and rs740603(G)-rs4818(G) haplotypes were associated with negative symptoms in the schizophrenic patients, particularly among female patients. Thus, the COMT gene polymorphisms may not contribute to the susceptibility to schizophrenia, but may contribute to the negative symptoms of schizophrenia among Han Chinese.
PMCID: PMC4190670  PMID: 22354729
Case-control; Association; Schizophrenia; COMT; Negative symptom
13.  Principal components methods for narrow-sense heritability in the analysis of multidimensional longitudinal cognitive phenotypes 
Genetic association studies of longitudinal cognitive phenotypes are an alternate approach to discovering genetic risk factors for Alzheimer’s disease. However, the standard linear mixed model approach is limited in the face of multidimensional longitudinal data and multiple genotypes. In this setting, the principal components of heritability (PCH) approach may increase efficiency by deriving a linear combination of phenotypes to maximize the heritability attributable to a particular genetic locus. The current study investigated the performance of two PCH methods, the Principal Components of Heritability Association Test (PCHAT) and C2BAT, in detecting association of the known Alzheimer’s disease susceptibility allele APOE-ε4 with cognitive function at baseline and decline in cognition over time.
PCHAT, C2BAT, and standard linear mixed models were used to test for association between APOE-ε4 allele and performance on 19 neuropsychological tests using subjects without dementia at baseline from the Religious Orders Study (ROS) (n=693) and Memory and Aging Project (MAP) (n=778). Analyses were conducted across the three methods for three nested phenotype definitions (all 19 measures, executive function and episodic memory measures, and episodic memory only), and for baseline data only vs. longitudinal change.
In all cases, APOE-ε4 was significantly associated with baseline level of and change over time in cognitive function, and PCHAT and C2BAT yielded evidence of association comparable to or stronger than conventional methods.
PCHAT, C2BAT, and other PCH methods may have utility for genetic association studies of multidimensional cognitive and other phenotypes by maximizing genetic information while limiting multiple comparisons.
PMCID: PMC3758806  PMID: 23650207
Principal components of heritability; multidimensional longitudinal data; cognitive decline; neuropsychological tests
14.  The Effects of a MAP2K5 MicroRNA Target Site SNP on Risk for Anxiety and Depressive Disorders 
Functional variants that contribute to genomewide association study (GWAS) signals are difficult to identify. MicroRNAs could contribute to some of these gene-trait relationships. We compiled a set of GWAS trait gene SNPs that were predicted to affect microRNA regulation of mRNA. Trait associations were tested in a sample of 6725 European-American (EA) and African-American (AA) subjects that were interviewed using the polydiagnostic SSADDA to diagnose major psychiatric disorders. A predicted miR-330-3p target site SNP (rs41305272) in mitogen-activated protein kinase kinase 5 (MAP2K5) mRNA was in LD (d’=1.0, r2=0.02) with a reported GWAS-identified variant for restless legs syndrome (RLS), a disorder frequently comorbid with anxiety and depression, possibly because of a shared pathophysiology. We examined the SNP’s association with mood and anxiety-related disorders. Rs41305272 was associated with agoraphobia (Ag) in EAs (odds ratio[OR]=1.95, p=0.007; 195 cases) and AAs (OR=3.2, p=0.03; 148 cases) and major depressive disorder (MDD) in AAs (OR=2.64, p=0.01; 427 cases), but not EAs (465 cases). Rs41305272*T carrier frequency was correlated with the number of anxiety and depressive disorders diagnosed per subject. RLS was not evaluated in our subjects. Predicted miR-330-3p target genes were enriched in pathways relevant to psychiatric disorders. These findings suggest that microRNA target site information may be useful in the analysis of GWAS signals for complex traits. MiR-330-3p and MAP2K5 are potentially important contributors to mood and anxiety-related traits. With support from additional studies, these findings could add to the large number of risk genes identified through association to medical disorders that have primary psychiatric effects.
PMCID: PMC4174417  PMID: 24436253
restless legs syndrome; depression; miR-330; MEK5; GWAS
15.  Preliminary Evidence of Ubiquitin Proteasome System Dysregulation in Schizophrenia and Bipolar Disorder: Convergent Pathway Analysis Findings from Two Independent Samples 
Schizophrenia (SCZ) and bipolar disorder (BPD) are polygenic disorders with many genes contributing to their etiologies. The aim of this investigation was to search for dysregulated molecular and cellular pathways for these disorders as well as psychosis. We conducted a blood-based microarray investigation in two independent samples with SCZ and BPD from San Diego (SCZ = 13, BPD = 9, control = 8) and Taiwan (SCZ = 11, BPD = 14, control = 16). Diagnostic groups were compared to controls, and subjects with a history of psychosis [PSYCH(+): San Diego (n = 6), Taiwan (n = 14)] were compared to subjects without such history [PSYCH(−): San Diego (n = 11), Taiwan (n = 14)]. Analyses of covariance comparing mean expression levels on a gene-by-gene basis were conducted to generate the top 100 significantly dysregulated gene lists for both samples by each diagnostic group. Gene lists were imported into Ingenuity Pathway Analysis (IPA) software. Results showed the ubiquitin proteasome pathway (UPS) was listed in the top ten canonical pathways for BPD and psychosis diagnostic groups across both samples with a considerably low likelihood of a chance occurrence (P = 0.001). No overlap in dysregulated genes populating these pathways was observed between the two independent samples. Findings provide preliminary evidence of UPS dysregulation in BPD and psychosis as well as support further investigation of the UPS and other molecular and cellular pathways for potential biomarkers for SCZ, BPD, and/or psychosis.
PMCID: PMC4165610  PMID: 19582768
ubiquitin; gene expression; biomarkers; micro-array; mRNA
16.  Contribution of Congenital Heart Disease to Neuropsychiatric Outcome in School-Age Children with 22q11.2 Deletion Syndrome 
Children with 22q11.2 deletion syndrome (22q11DS) present with congenital heart disease (CHD) and high prevalence of psychiatric disorders and neurocognitive deficits. Although CHD has been implicated in neurodevelopment, its role in the neuropsychiatric outcome in 22q11DS is poorly understood. We investigated whether CHD contributes to the high prevalence of psychiatric disorders and neurocognitive impairments in 22q11DS. Fifty-four children ages 8–14 years with 22q11DS and 16 age-matched non-deleted children with CHD participated. They were assessed using semi-structured interviews and a Computerized Neurocognitive Battery. CHD status was assessed using available medical records. Prevalence of psychiatric disorders and cognitive profiles were compared among the groups. There were no significant differences between the prevalence of psychiatric disorders in the 22q11DS with and without CHD. In 22q11DS with CHD, the prevalence rates were 41% anxiety disorders, 37% ADHD and 71% psychosis spectrum. In 22q11DS without CHD, the rates were 33% anxiety disorders, 41% ADHD and 64% psychosis spectrum. In comparison, the non-deleted CHD group had lower rates of psychopathology (25% anxiety disorders, 6% ADHD, and 13% psychosis spectrum). Similarly, the 22q11DS groups, regardless of CHD status, had significantly greater neurocognitive deficits across multiple domains, compared to the CHD-only group. We conclude that CHD in this sample of children with 22q11.2DS does not have a major impact on the prevalence of psychiatric disorders and is not associated with increased neurocognitive deficits. These findings suggest that the 22q11.2 deletion status itself may confer significant neuropsychiatric vulnerability in this population.
PMCID: PMC4154196  PMID: 24265253
22q11.2 deletion syndrome; congenital heart disease; psychiatric disorder; psychosis spectrum; neuropsychology
17.  White matter changes in basis pontis in small expansion FMR1 allele carriers with parkinsonism 
Examples of white matter hyperintensities (wmh) on magnetic resonance images in a basis pontis are presented in two male carriers, each of whom carry a small CGG expansion Fragile X Mental Retardation (FMR1) allele. One carried a premutation (PM) allele of 85 CGG repeats and the other, a grey zone (GZ) allele of 47 repeats. Both were originally diagnosed with idiopathic Parkinson’s Disease (iPD). Similar changes are also shown in one PM carrier of 99 repeats affected with mild tremor and imbalance, who was ascertained through a fragile X syndrome family. These examples draw attention to the occurrence of wmh in a basis pontis in the carriers of small CGG expansions presenting with tremor and ataxia. Moreover, the presence of this change in GZ, as well as PM, allele carriers originally diagnosed with iPD supports our earlier suggestion that both these alleles may contribute to the neurodegerative changes in this disorder which, in the examples presented, have been reflected by wmh, most prominent in the cerebellar peduncles and/or pontine area.
PMCID: PMC4148303  PMID: 21445959
MRI changes; Parkinson’s Disease; Fragile X
18.  Polymorphisms in the GRIA1 Gene Region in Psychotic Bipolar Disorder 
We reported previously a significant linkage signal between psychotic bipolar disorder (BP) and microsatellite markers on chromosome 5q31–34 in the National Institute of Mental Health Bipolar Genetics Initiative (NIMH-BPGI) data set, Wave 1. In an attempt to fine-map this linkage signal we genotyped 1,134 single nucleotide polymorphisms (SNPs) under the linkage peak in 23 informative families (131 individuals) with evidence of linkage. We tested family based association in the presence of linkage with the computer software package FBAT. The most significant association in these families was with a SNP in the second intron of GRIA1 (α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) subunit 1 receptor gene) (rs490922, Z-score = 3.3, P= 0.001). The analysis of 37 additional families with psychotic BP from NIMH-BPGI data sets, Waves 2, 3, and 4 revealed a signal at a SNP in intron 5 of the GRIA1 gene (rs4385264, Z-score = 3.2, P-value = 0.002). A combined analysis of all 60 families continued to support evidence for association of GRIA1 with psychotic BP; however, individual SNPs could not be replicated across datasets. The AMPA1 receptor has been shown to influence cognitive function, such as working memory and reward learning. Our findings suggest that variations in this receptor may contribute to the pathophysiology of BP with psychotic features in some families.
PMCID: PMC4130207  PMID: 18484081
genetic; linkage; association; mood disorder; glutamate receptor
19.  Sleep apnea in fragile X premutation carriers with and without FXTAS 
This report seeks to establish the prevalence of sleep apnea in patients with the FMR1 premutation with and without FXTAS and to determine any correlation between CGG repeat and FMR1 mRNA levels with sleep apnea prevalence. Demographic and medical data from 430 (229 males, 201 females) participants were used in this analysis. Participants included premutation carriers with (n=118) and without FXTAS (n=174) as well as controls without the premutation (n=123). Logistic regression models were employed to estimate the odds ratio of sleep apnea relative to controls, adjusted for age and gender, and also to examine potential association with CGG size and FMR1 mRNA expression level. The observed proportion of sleep apnea in premutation carriers with and without FXTAS and controls are 31.4% (37/118), 8.6% (15/174), and 13.8% (17/123), respectively. The adjusted odds of sleep apnea for premutation carriers with FXTAS is about 3.4 times that compared to controls (odds ratio, OR=3.4, 95% CI 1.8 to 7.4; p=0.001), and similarly relative to premutation carriers without FXTAS (OR=2.9, 95% CI 1.2 to 6.9; p=0.014). The risk of sleep apnea was not different between controls and premutation carriers without FXTAS. The presence of sleep apnea is not associated with CGG repeat numbers nor FMR1 mRNA expression level among premutation carriers. Our data supports a higher prevalence and risk of sleep apnea in patients with FXTAS. We recommend that all patients diagnosed with FXTAS be screened for sleep apnea given the negative and perhaps accelerative impact sleep apnea may have on their FXTAS progression.
PMCID: PMC4109408  PMID: 21932336
sleep apnea; fragile X-associated tremor/ataxia syndrome; trinucleotide repeat diseases; mitochondrial disorders; gait disorders/ataxia
20.  From the Black Widow Spider to Human Behavior: Latrophilins, a Relatively Unknown Class of G Protein-Coupled Receptors, Are Implicated in Psychiatric Disorders 
The findings of a recent study associate LPHN3, a member of the latrophilin family, with an increased risk of developing attention deficit/hyperactivity disorder (ADHD), the most common psychiatric disorder in childhood and adolescence. Latrophilins comprise a new family of G protein-coupled receptors of unknown native physiological function that mediate the neurotoxic effects of α-latrotoxin, a potent toxin found in black widow spider venom. This receptor–toxin interaction has helped to elucidate the mechanistic aspects of neurotransmitter and hormone release in vertebrates. Such unprecedented discovery points to a new direction in the assessment of ADHD and suggest that further study of this receptor family may provide novel insights into the etiology and treatment of ADHD and other related psychiatric conditions.
PMCID: PMC4101183  PMID: 21184579
ADHD; LPHN3; latrophilin; G protein-coupled receptor; α-latrotoxin
21.  Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism 
Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB).
We conducted dense transmission disequilibrium mapping of the 15q11-q13 region with 93 single nucleotide polymorphisms (SNPs) in 86 strictly defined autism trios and tested association between SNPs and autism using the transmission disequilibrium test (TDT). As exploratory analyses, parent-of-origin effects were examined using likelihood-ratio tests (LRT) and genotype-phenotype associations for specific RRB using the Family-Based Association Test (FBAT). Additionally, gene-gene interactions between nominally associated 15q11-q13 variants and 5-HTTLPR, the common length polymorphism of SLC6A4, were examined using conditional logistic regression (CLR).
TDT revealed nominally significant transmission disequilibrium between autism and five SNPs, three of which are located within close proximity of the GABAA receptor subunit gene clusters. Three SNPs in the SNRPN/UBE3A region had marginal imprinting effects. FBAT for genotype-phenotype relations revealed nominally significant association between two SNPs and one ADI-R sub-domain item. However, both TDT and FBAT were not statistically significant after correcting for multiple comparisons. Gene-gene interaction analyses by CLR revealed additive genetic effect models, without interaction terms, fit the data best.
Lack of robust association between the 15q11-q13 SNPs and RRB phenotypes may be due to a small sample size and absence of more specific RRB measurement. Further investigation of the 15q11-q13 region with denser genotyping in a larger sample set may be necessary to determine whether this region confers risk to autism, indicated by association, or to specific autism phenotypes.
PMCID: PMC4095800  PMID: 18361419
Autism; 15q11-q13; restricted repetitive behavior; 5-HTTLPR; association
22.  Selected Rapporteur Summaries from the XX World Congress of Psychiatric Genetics, Hamburg, Germany, October 14-18, 2012 
The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14-18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG.
PMCID: PMC4090768  PMID: 23341144
International Society of Psychiatric Genetics; World Congress of Psychiatric Genetics; Sequencing; DNA; SCZ; PTSD; Substance Abuse; Pharmacogenomics
23.  Associations of the 5-hydroxytryptamine (Serotonin) Receptor 1B Gene (HTR1B) with Alcohol, Cocaine, and Heroin Abuse 
Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5-hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5-HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To clarify the roles of commonly-reported single nucleotide polymorphisms (SNPs) of the HTR1B gene underlying alcohol and drug dependence (abuse), we performed a meta-analysis based on the available genotype data from individual candidate gene-based association studies. Evidence of association was found between the functional SNP -161A>T (rs130058) and alcohol, cocaine, and heroin dependence (e.g., P = 0.03 and odds ratio = 1.2 (1.02, 1.42) in the combined European, Asian, African, and Hispanic populations). SNP -261T>G (rs11568817) also showed evidence of association but with different directions in Europeans and non-Europeans (e.g., P = 0.0018 with odds ratio = 1.42 (1.14, 1.76) and P = 0.01 with odds ratio = 0.5 (0.3, 0.85), respectively). This meta-analysis supports the associations of HTR1B -261T>G and -161A>T with alcohol and drug abuse and further investigations are warranted in larger samples.
PMCID: PMC4089973  PMID: 23335468
Substance Use Disorder; Addiction; Meta-analysis; Association; Linkage Disequilibrium
24.  A Genome-Wide Association Study of Sleep Habits and Insomnia 
Several aspects of sleep behaviour such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of 6 sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317K, 370K and 610K arrays and the common Single Nucleotide Polymorphisms between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the 3rd intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (p = 1.3 × 10−6). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (p = 0.73). We have identified several other associations that await replication in an independent sample. Our study had good power to detect common single nucleotide polymorphisms that explain more than 2% of the phenotypic variance in self-report sleep phenotypes at a genome-wide significant level. No such variants were detected.
PMCID: PMC4083458  PMID: 23728906
insomnia; genetics; mood; sleep; circadian
25.  FMR1 CGG Expansions: Prevalence and Sex Ratios 
We have estimated the prevalence of FMR1 premutation and gray zone CGG repeat expansions in a population-based sample of 19,996 male and female adults in Wisconsin and compared the observed sex ratios of the prevalence of FMR1 CGG premutation and gray zone expansions to theoretical sex ratios. The female premutation prevalence was 1 in 148 and comparable to past research, but the male premutation prevalence of 1 in 290 is somewhat higher than most previous estimates. The female:male premutation prevalence ratio is in line with the theoretically predicted sex ratio. The prevalence of CGG repeats in the gray zone (45–54 repeats) was 1 in 33 females and 1 in 62 males. The prevalence of the “expanded” gray zone (defined here as 41–54 CGG repeats) was 1 in 14 females and 1 in 22 males, leading to a female:male ratio of 1.62 (95% confidence interval 1.39–1.90). This female:male ratio was significantly lower than the expected ratio of 2.0. We examined results from three previously published FMR1 prevalence studies and found similar female:male ratios for CGG repeats in this “expanded” gray zone range (pooled female:male ratio across all four studies 1.66, 95% confidence interval 1.51–1.82). Further research is needed to understand the apparent excess prevalence of males with CGG repeats in this range.
PMCID: PMC3885228  PMID: 23740716
Fragile X; gray zone; premutation; FMR1

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