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1.  MACROD2 gene associated with autistic-like traits in a general population sample 
Psychiatric genetics  2014;24(6):241-248.
There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0 × 10−5. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.
PMCID: PMC4320645  PMID: 25360606
association; autistic-like traits; MACROD2; Raine study; single nucleotide polymorphism
2.  [No title available] 
PMCID: PMC3870040  PMID: 24257701
3.  κ-opioid Receptor Gene as a Predictor of Response in a Cocaine Vaccine Clinical Trial 
Psychiatric genetics  2013;23(6):10.1097/YPG.0000000000000008.
We examined a pharmacogenetic association between a variant in the κ-opioid receptor (OPRK1) gene and the response to treatment with a cocaine vaccine tested in a recent clinical trial. This gene has a protective allele for opiate addiction that may act by inhibiting dopamine activation associated with reinforcement.
Sixty-nine DNA samples were obtained from 114 cocaine and opioid dependent subjects who were enrolled in a 16 week Phase IIb randomized double-blind placebo-controlled trial and who received five vaccinations over the first 12 weeks. We genotyped 66 of these subjects for the rs6473797 variant of the OPRK1 gene and we compared vaccine to placebo subjects in terms of cocaine-free urines over time.
Using repeated measures analysis of variance, corrected for population structure, vaccine pharmacotherapy reduced cocaine positive urines significantly based on OPRK1 genotype. In subjects treated with the cocaine vaccine, those who were homozygous for the protective A allele of rs6473797 had the proportion of positive urines drop from 78% to 51% on vaccine (point-wise P < .0001, experiment-wise P <.005), while the positive urines of those individuals carrying the non-protective, risk G allele dropped from 82% to 77%. Strong interactions of treatment by SNP (single nucleotide polymorphism) reflected a lower baseline and significant reduction for placebo subjects with the risk G allele (P <0.00001).
This study indicates that a patient’s OPRK1 genotype could be used to identify a subset of individuals for which vaccine treatment may be an effective pharmacotherapy for cocaine dependence.
PMCID: PMC3885873  PMID: 23995774
Gene; vaccine; polymorphism; cocaine; treatment; opioid
4.  Sex chromosome-wide association analysis suggested male-specific risk genes for alcohol dependence 
Psychiatric genetics  2013;23(6):233-238.
Alcohol dependence is more common among men than among women. Potential explanations for this male excess include a role of genes on sex chromosomes (X and Y). In the present study, we scanned the entire Y chromosome and its homologues on X chromosome in males, in order to identify male-specific risk genes for alcohol dependence. Two thousand nine hundred twenty-seven subjects in two independent cohorts were analyzed. The European-American male cohort [883 cases with alcohol dependence and 445 controls] served as the discovery cohort and the European-American female cohort [526 cases and 1,073 controls] served as a contrast group. All subjects were genotyped on the Illumina Human 1M beadchip. Two thousand two hundred twenty-four SNPs on Y chromosome or in the homologues on X chromosome were analyzed. The allele frequencies were compared between cases and controls within each cohort using logistic regression analysis. We found that, after experiment-wide correction, 2 SNPs on the X chromosome were significantly associated with alcohol dependence in European-American males (p=1.0×10-4 for rs5916144 and p=5.5×10−5 for rs5961794 at 3'UTR of NLGN4X), but not in females. A total of twenty-six SNPs at 3'UTR of or within NLGN4X were nominally associated with alcohol dependence in males (5.5×10−5≤p≤p0.05), all of which were not statistically significant in females. We conclude that NLGN4X was a significant male-specific risk gene for alcohol dependence in European-Americans. NLGN4X might harbor a causal variant(s) for alcohol dependence. A defect of synaptogenesis in neuronal circuitry caused by NLGN4X mutations is believed to play a role in alcohol dependence.
PMCID: PMC3941913  PMID: 23907288
Alcohol dependence; NLGN4X; Y chromosome; Homologue; Male-specificity; Synaptogenesis
5.  Association between AVPR1A, DRD2, and ASPM and Endophenotypes of Communication Disorders 
Psychiatric genetics  2014;24(5):191-200.
Speech sound disorder (SSD) is one of the most common communication disorders, with prevalence rates of 16% at 3 years of age, and an estimated 3.8% of children still presenting speech difficulties at 6 years of age. Several studies have identified promising associations between communication disorders and genes in brain and neuronal pathways, but there have been few studies focusing on SSD and its associated endophenotypes. Based on the hypothesis that neuronal genes may influence endophenotypes common to communication disorders, we focused on three genes related to brain and central nervous system functioning: dopamine D2 receptor (DRD2), arginine-vassopressin receptor 1a (AVPR1A), and microcephaly gene ASPM.
We examined the association of these genes with key endophenotypes of SSD – phonological memory measured by multisyllabic and nonword repetition, vocabulary measured by Expressive One Word Picture Vocabulary Test (EOWPVT) and Peabody Picture Vocabulary Test (PPVT), and reading decoding measured by Woodcock Reading Mastery Tests Revised – as well as the clinical phenotype of SSD. We genotyped tag SNPs in these genes and examined 498 individuals from 180 families.
These data show several SNPs in all three genes were associated with phonological memory, vocabulary, and reading decoding with p<0.05. Notably, associations in AVPR1A (rs11832266) were significant after multiple testing correction. Gene-level tests showed DRD2 was associated with vocabulary, ASPM with vocabulary and reading decoding, and AVPR1A with all three endophenotypes.
Endophenotypes common to SSD, language impairment, and reading disability are all associated with these neuronal pathway genes.
PMCID: PMC4141900  PMID: 24849541
neural genes; phonology; speech impairment; language development; genetics
6.  Genetic association between RGS1 and internalizing disorders 
Psychiatric genetics  2013;23(2):56-60.
Quantitative trait loci identified in animal models provide potential candidate susceptibility loci for human disorders. In this study, we investigated whether internalizing disorders (anxiety disorders, major depression, and neuroticism) were associated with a region on human chromosome 1 syntenic with a quantitative trait locus for rodent emotionality.
We genotyped 31 single-nucleotide polymorphisms in genes located on chromosome 1q31.2 in a two-stage association study of 1128 individuals chosen for a high or a low genetic risk for internalizing disorders from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.
None of the individual single-nucleotide polymorphisms showed consistent association across stages. A four-marker haplotype in the regulator of G-protein signaling 1 gene (RGS1) was significantly associated with decreased internalizing risk in both stages, whereas another showed a nominal association with a higher risk.
Our data suggest that markers in the RGS1 gene might be in linkage disequilibrium with a protective allele that reduces the risk of anxiety and depressive disorders.
PMCID: PMC3606916  PMID: 23324853
anxiety; association study; depression; genetics; personality
7.  Association study of the β-arrestin 2 gene (ARRB2) with opioid and cocaine dependence in a European American population 
Psychiatric genetics  2012;22(3):141-145.
The rewarding properties of drugs of abuse are mediated by the Mu-Opioid Receptor (MOR). Genetic variation in MOR and MOR interacting proteins (MORIPs) involved in MOR signaling may increase risk for drug dependence. The MORIP, B-arrestin, plays an important role in the regulation of MOR trafficking thereby highlighting it as a candidate gene for addiction phenotypes. In this case-control association study, DNA samples from cocaine (n=336) and opioid-dependent (n=335) patients and controls (n=656) were genotyped for 7 single nucleotide polymorphisms (SNPs) (rs11868227, rs3786047, rs4522461, rs1045280, rs2271167, rs2036657, and rs4790694) across ARRB2, the gene encoding the B-arrestin 2 protein. No significant differences were observed in genotype or allele frequency between drug dependent and control individuals for any of the SNPs analyzed. Haplotype analysis was similarly negative. Further studies are needed to determine whether variation in ARRB2 (or other MORIPs) are relevant to cocaine or opioid dependence in different ethnic populations or if they confer risk that is specific to dependence on other drugs of abuse.
PMCID: PMC3920286  PMID: 22472784
case-control association study; cocaine dependence; opioid dependence; AARB2
8.  Variants in the 15q25 gene cluster are associated with risk for schizophrenia and bipolar disorder 
Psychiatric genetics  2013;23(1):20-28.
Rates of tobacco smoking are significantly higher in patients with schizophrenia compared with the general population. The underlying mechanism for this comorbidity is unclear. One hypothesis is that there are common genetic factors that predispose to both nicotine dependence (ND) and schizophrenia. To investigate this hypothesis, we examined the association of the 15q25 gene cluster, the most significant candidate region to date implicated in ND and smoking behavior, with schizophrenia and bipolar disorder.
Five variants in the 15q25 gene cluster (rs951266, rs16969968, rs1051730, rs8040868, and rs17477223) were selected to test for association with schizophrenia diagnosis, bipolar disorder diagnosis, and the presence of negative symptoms of schizophrenia. Effects of the variants on 15q25 gene expression were analyzed using publically available postmortem brain expression data.
A meta-analysis revealed four markers associated with risk for schizophrenia and bipolar disorder (rs951266, rs16969968, rs8040868, and rs17477223), and with the presence of negative symptoms of schizophrenia (rs951266, rs1051730, rs8040868, and rs17477223). The associations were in the same direction as that found for ND. Gene expression analysis indicated an association between genotypes of the rs1051730 variant and CHRNA5 expression in brain and peripheral blood mononuclear cells, and with the rs16969968 and rs17477223 variants in brain.
Variants in the 15q25 gene cluster are associated with risk for schizophrenia/bipolar illness, negative symptoms of schizophrenia, and influence CHRNA5 expression in the brain and peripheral blood mononuclear cells. These results are consistent with the notion that there are genetic mechanisms common to schizophrenia, ND, and bipolar disorder.
PMCID: PMC3644701  PMID: 23196875
15q25 gene cluster; bipolar disorder; CHRNA5; nicotine dependence; schizophrenia
9.  Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia 
Psychiatric genetics  2012;22(1):10.1097/YPG.0b013e32834c0c33.
The chromosomal region, 15q13-q14, including the α7 nicotinic acetylcholine receptor gene, CHRNA7, is a replicated region for schizophrenia. This study fine-mapped genes at 15q13-q14 to determine whether the association is unique to CHRNA7.
Family-based and case–control association studies were performed on Caucasian-non-Hispanic and African-American individuals from 120 families as well as 468 individual patients with schizophrenia and 144 well-characterized controls. Single-nucleotide polymorphism (SNP) markers were genotyped, and association analyses carried out for the outcomes of schizophrenia, smoking, and smoking in schizophrenia.
Three genes were associated with schizophrenia in both ethnic populations: TRPM1, KLF13, and RYR3. Two SNPs in CHRNA7 were associated with schizophrenia in African-Americans, and a second SNP in CHRNA7 was significant for an association with smoking and smoking in schizophrenia in Caucasians.
Results of these studies support association of the 15q13-q14 region with schizophrenia. The broad positive association suggests that more than one 15q gene may be contributing to the disorder, either in combination or through a regulatory mechanism. Psychiatr Genet 22:1–14 © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
PMCID: PMC3878876  PMID: 21970977
association; CHRNA7; chromosome 15; copy number variation; nicotinic receptor; schizophrenia
10.  A large-scale candidate gene analysis of mood disorders: evidence of neurotrophic tyrosine kinase receptor and opioid receptor signaling dysfunction 
Psychiatric genetics  2013;23(2):10.1097/YPG.0b013e32835d7028.
Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case–control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort.
We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated.
Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, κ1 (OPRK1).
This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings.
PMCID: PMC3869619  PMID: 23277131
linkage and association; mood disorders; neurotrophic tyrosine kinase receptor; opioid receptor; type 2; κ1
12.  Chryptochrome 2 Variants, Chronicity, and Seasonality of Mood Disorders 
Psychiatric genetics  2012;22(6):305-306.
PMCID: PMC3485578  PMID: 23111457
13.  Evidence for association of two variants of the nociceptin/orphanin FQ receptor gene OPRL1 with vulnerability to develop opiate addiction in Caucasians 
Psychiatric genetics  2010;20(2):10.1097/YPG.0b013e32833511f6.
The OPRL1 gene encodes the nociceptin/orphanin FQ receptor (NOP-R), which plays a role in regulating tolerance and behavioral responses to morphine. However, there is limited information on whether variants of OPRL1 are associated with vulnerability to develop opiate addiction. In this study, we examined five variants of OPRL1 and their role in determining vulnerability to develop opiate addiction.
We recruited 447 subjects: 271 former severe heroin addicts and 176 healthy controls. Using a 5′-fluorogenic exonuclease assay (TaqMan®), we genotyped subjects at five variants in OPRL1. It was then determined whether there was a significant association of allele, genotype, or haplotype frequency with vulnerability to develop opiate addiction.
When the cohort was stratified by ethnicity, we found that, in Caucasians but not in African Americans or Hispanics, the allele frequency of rs6090041 and rs6090043 were significantly associated point-wise with opiate addiction (P = 0.03 and 0.04, respectively). Of the haplotypes formed by these two variants, one haplotype was found to be associated with protection from developing opiate addiction in both African Americans (point-wise P = 0.04) and Caucasians (point-wise P = 0.04), and another haplotype with vulnerability to develop opiate addiction in Caucasians only (P = 0.020).
This study provides evidence for an association of two variants of the OPRL1 gene, rs6090041 and rs6090043, with vulnerability to develop opiate addiction, suggesting a role for NOP-R in the development of opiate addiction.
PMCID: PMC3832186  PMID: 20032820
OPRL1; ORL1; nociceptin/orphanin FQ receptor; polymorphism; variant; opiate addiction; heroin
14.  Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction 
Psychiatric genetics  2010;20(5):10.1097/YPG.0b013e32833a2106.
We have used genome-wide association studies to identify variants that are associated with vulnerability to develop heroin addiction.
DNA from 325 methadone stabilized, former severe heroin addicts and 250 control subjects were pooled by ethnicity (Caucasian and African American) and analyzed using the Affymetrix GeneChip Mapping 100K Set. Genome-wide association tests were conducted.
The strongest association with vulnerability to develop heroin addiction, with experiment-wise significance (P = 0.035), was found in Caucasians with the variant rs10494334, a variant in an unannotated region of the genome (1q23.3). In African Americans, the variant most significantly associated with heroin addiction vulnerability was rs950302, found in the cytosolic dual specificity phosphatase 27 gene DUSP27 (point-wise P = 0.0079). Furthermore, analysis of the top 500 variants with the most significant associations (point-wise P ≤ 0.0036) in Caucasians showed that three of these variants are clustered in the regulating synaptic membrane exocytosis protein 2 gene RIMS2. Of the top 500 variants in African Americans (point-wise P ≤ 0.0238), three variants are in the cardiomyopathy associated 3 gene CMYA3.
This study identifies new genes and variants that may increase an individual’s vulnerability to develop heroin addiction.
PMCID: PMC3832188  PMID: 20520587
Addiction; gene; heroin; microarray; polymorphism
15.  Motor sequencing deficit as an endophenotype of speech sound disorder: A genome-wide linkage analysis in a multigenerational family 
Psychiatric genetics  2012;22(5):226-234.
The purpose of this pilot study was to investigate a measure of motor sequencing deficit as a potential endophenotype of speech sound disorder (SSD) in a multigenerational family with evidence of familial SSD.
In a multigenerational family with evidence of a familial motor-based SSD, affectation status and a measure of motor sequencing during oral motor testing were obtained. To further investigate the role of motor sequencing as an endophenotype for genetic studies, parametric and nonparametric linkage analyses were conducted using a genome-wide panel of 404 microsatellites.
In seven of the ten family members with available data, SSD affectation status and motor sequencing status coincided. Linkage analysis revealed four regions of interest, 6p21, 7q32, 7q36, and 8q24, primarily identified with the measure of motor sequencing ability. The 6p21 region overlaps with a locus implicated in rapid alternating naming in a recent genome-wide dyslexia linkage study. The 7q32 locus contains a locus implicated in dyslexia. The 7q36 locus borders on a gene known to affect component traits of language impairment.
Results are consistent with a motor-based endophenotype of SSD that would be informative for genetic studies. The linkage results in this first genome-wide study in a multigenerational family with SSD warrant follow-up in additional families and with fine mapping or next-generation approaches to gene identification.
PMCID: PMC3407825  PMID: 22517379
speech sound disorder; multigenerational family; genome-wide linkage analysis; sequential motor speech task; 6p21; 7q32; 7q36; 8q24
16.  Genome-wide Linkage Scan of Antisocial Behavior, Depression and Impulsive Substance Use in the UCSF Family Alcoholism Study 
Psychiatric genetics  2012;22(5):235-244.
Epidemiological and clinical studies suggest that rates of antisocial behavior, depression, and impulsive substance use are increased among individuals diagnosed with alcohol dependence relative to those who are not. Thus, the present study conducted genome-wide linkage scans of antisocial behavior, depression, and impulsive substance use in the University of California at San Francisco Family Alcoholism Study.
Antisocial behavior, depressive symptoms, and impulsive substance use were assessed using three scales from the MMPI-2, the Antisocial Practices content scale (ASP), the Depression content scale (DEP), and the revised MacAndrew Alcoholism scale (MAC-R). Linkage analyses were conducted using a variance components approach.
Suggestive evidence of linkage to three genomic regions independent of alcohol and cannabis dependence diagnostic status was observed: the ASP scale showed evidence of linkage to chromosome 13 at 11 cM, the MAC-R scale showed evidence of linkage to chromosome 15 at 47 cM, and all 3 scales showed evidence of linkage to chromosome 17 at 57–58 cM.
Each of these regions has shown prior evidence of linkage and association to substance dependence as well as other psychiatric disorders such as mood and anxiety disorders, ADHD, and schizophrenia thus suggesting potentially broad relations between these regions and psychopathology.
PMCID: PMC3427472  PMID: 22517380
Genetic Linkage; Depressive Symptoms; Antisocial Practices; Substance Use Disorders; MMPI-2
17.  Linkage analysis of alternative anxiety phenotypes in multiply affected panic disorder families 
Psychiatric genetics  2012;22(3):123-129.
The choice of phenotype definitions for genetic studies of panic and phobic disorders is complicated by family, twin and neurobiological data indicating both distinct and shared risk factors as well as heterogeneity within categories. We previously reported a genome scan in 120 multiplex panic disorder (PD) families using a phenotype that closely adhered to the DSM IV PD definition. Here we extend this work by conducting exploratory linkage analyses in this same pedigree set using ten additional literature- based panic and phobia-related phenotypes that take into account aspects of these hypothesized complexities.
Multiply affected families (> 2 individuals with PD) were recruited from clinical and non-clinical sources, evaluated by clinician administered semi-structured interview and subsequent blind consensus best estimate procedure. Each phenotype was analyzed under dominant and recessive models using parametric 2-point (homogeneity and heterogeneity), multipoint, and non-parametric methods. Empirically based permutations were used to estimate model specific and global (across all phenotypes) p-values.
The highest score was a 2-point lod (4.27, global p < 0.08) on chromosome 13 (D13S793, 76cM) for the phenotype “specific or social phobia” under a recessive model and conditions of homogeneity. There was minimal support for linkage to any of the remaining nine phenotypes.
Though interpretation of findings is limited by sample size and the large number of phenotypes and models analyzed these data suggest a region on chromosome 13 as a potential site for further exploration in relation to risk for specific and social phobias.
PMCID: PMC3767163  PMID: 22525237
panic; linkage; anxiety; specific phobia; social phobia; phenotype
18.  Involvement of PTPN5, the gene encoding the STriatal-Enriched protein tyrosine Phosphatase (STEP), in schizophrenia and cognition 
Psychiatric genetics  2012;22(4):168-176.
STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific member of the PTP family that has been implicated in learning and memory. In this study, we examined the association of the PTPN5 (protein-tyrosine-phosphatase non-receptor 5) gene, which encodes for STEP, with both schizophrenia and cognitive functioning in the Israeli Jewish population.
A 868 subjects schizophrenia (SZ) case-control study was performed (286 cases and 582 controls). Eleven STEP tagging SNPs were selected, and single markers and haplotypes association analyses were performed. A cognitive variability study included 437 healthy females who completed a computerized cognitive battery. We performed univariate associations between the SNPs and cognitive performance. The possible functional role of these variants was examined by studying their association with gene expression levels in the brain.
In the SZ study, we found nominal association in the whole sample between rs4075664 and SZ. SZ males showed a more significant association for 3 SNPs (rs4075664, rs2278732, rs4757710). Haplotypes of the studied SNPs were associated with SZ both in the overall sample and within the male sub-sample. Expression analysis provided some support for the effects of the associated SNPs on PTPN5 expression level. The cognitive variability study showed positive associations between PTPN5 SNPs and different cognitive subtests. Principal component analysis demonstrated an “Attention Index” neurocognitive component that was associated with two SNP pairs (rs10832983*rs10766504 and rs7932938*rs4757718).
The results imply a model in which PTPN5 may play a role in normal cognitive functioning and contributes to aspects of the neuropathology of schizophrenia.
PMCID: PMC3760343  PMID: 22555153
schizophrenia; PTPN5; psychiatric genetics; cognitive function; association study
19.  Microduplications Disrupting the MYT1L Gene (2p25.3) are Associated with Schizophrenia 
Psychiatric Genetics  2012;22(4):206-209.
Childhood-onset schizophrenia (COS) is a rare severe form of schizophrenia that may have greater salient genetic risk. Despite evidence for high heritability, conclusive genetic causes of schizophrenia remain elusive. Recent genomic technologies in concert with large case-control cohorts, have led to several associations of highly penetrant rare copy number variants (CNVs) and schizophrenia. We previously reported two patients with COS who carried a microduplication disrupting the PXDN and MYT1L genes at 2p25.3. This is a significantly higher rate of duplications within our COS population (N=92) when compared to 2,026 healthy controls (p=0.002). As a replication, we report a meta-analysis of four recently published studies that together provide strong evidence for association between variably-sized microduplications involving the MYT1L gene and schizophrenia. None have reported this separately. Altogether, among 5,325 cases and 9,279 controls, 10 microduplications were observed; 9 in cases and 1 in a control (OR=15.7, p=0.001). Further, the 2% rate observed in our COS patients is also significantly higher than the rate in adult onset cases (0.14%, OR=16.6, p=0.01). This report adds to the growing body of literature implicating rare CNVs as risk factors for schizophrenia, and that some risk CNVs are more common among extreme early-onset cases.
PMCID: PMC3384746  PMID: 22547139
CNV; childhood-onset schizophrenia; 2p25.3; MYT1L; PXDN; 1M Illumina SNP microarray
20.  Polymorphisms in the maternal sex steroid pathway are associated with behavior problems in male offspring 
Psychiatric Genetics  2012;22(3):115-122.
Slight perturbations in maternal sex steroid production and metabolism may interfere with normal fetal neurodevelopment. The balance of maternal estrogens and androgens may have direct fetal effects, may influence the fetal hypothalamic-pituitary-gonadal axis or may alter local hormonal activity within the fetal brain. We investigated maternal functional polymorphisms of CYP17, CYP19 and CYP1B1, which control three major enzymatic steps in sex steroid biosynthesis and metabolism, in relation to childhood behaviors.
The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic urban pregnancy cohort from 1998–2002 (n = 404). DNA was obtained from maternal blood (n=149) and from neonatal cord blood (n=53). At each visit, mothers completed the Behavior Assessment System for Children (BASC), a parent-reported questionnaire used to evaluate children for behavior problems. We focused on problem behaviors more commonly associated with ADHD (hyperactivity, attention problems, externalizing behaviors, conduct disorder, poor adaptability) to see if maternal genetic variants in sex steroid production and metabolism influence sexually-dimorphic behaviors in offspring.
The more active gene variants were significantly associated with Attention Problems and poorer Adaptive Skills in male compared to female offspring. The CYP19 variant allele was also significantly associated with worse scores for boys on the Hyperactivity, Externalizing Problems Composite and Adaptive Skills Composite scales (p < 0.05).
We observed maladaptive behaviors in the male offspring of mothers who carried functional polymorphisms in the sex steroid pathway. The strongest associations were in domains commonly affected in Attention Deficit-Hyperactivity Disorder.
PMCID: PMC3335953  PMID: 22336992
single nucleotide polymorphism; estradiol; androgen; BASC; attention deficit-hyperactivity disorder; 17-alpha-hydroxylase; aromatase; cytochrome P-450; CYP1B1
21.  [No title available] 
PMCID: PMC3643116  PMID: 19672139
22.  Genetic Associations between Neuregulin-1 SNPs and Neurocognitive Function in Multigenerational, Multiplex Schizophrenia Families 
Psychiatric Genetics  2012;22(2):70-81.
Recent work shows promising associations between schizophrenia and polymorphisms in Neuregulin-1 (NRG1) and a large literature also finds strong familial relationships between schizophrenia and cognitive deficits. Given the role of NRG1 in glutamate regulation and glutamate’s effect on cognition, we hypothesized that cognitive deficits may be related to variation within NRG1, providing a possible mechanism to increase risk for schizophrenia.
This study examined the associations between NRG1, cognition, and schizophrenia using a multigenerational multiplex family sample (total N = 419, 40 families), including 58 affected participants (schizophrenia or schizoaffective disorder-depressed type) and their 361 unaffected relatives. Participants were genotyped for 40 NRG1 single nucleotide polymorphisms (SNPs), chosen largely based on previous associations with schizophrenia. All participants completed structured diagnostic interviews and a computerized neurocognitive battery assessing eight cognitive domains. Variance component quantitative trait analyses tested for associations between individual NRG1 SNPs and cognitive performance in the total sample, a subsample of healthy participants with no DSM diagnosis, and using general intelligence as a covariate.
Effect sizes (within-family beta coefficients) ranged from 0.08 to 0.73, and 61 of these associations were nominally significant (p≤.05), with 12 associations at p≤.01, although none achieved the modified Bonferroni significance threshold of p<.0003. Attention was the most frequently nominally associated domain and rs10503929, a non-synonymous SNP, was the most frequently nominally associated SNP.
Although not significant experiment-wise, these findings suggest that further study of the associations between variation in NRG1 and cognition may be productive.
PMCID: PMC3290679  PMID: 22183611
NRG1; attention; rs10503929
23.  Test of Association Between 10 SNPs in the Oxytocin Receptor Gene and Conduct Disorder 
Psychiatric Genetics  2012;22(2):99-102.
Animal and human studies have implicated oxytocin (OXT) in affiliative and prosocial behaviors. We tested whether genetic variation in the OXT receptor (OXTR) gene is associated with conduct disorder (CD).
Utilizing a family-based sample of adolescent probands recruited from an adolescent substance abuse treatment program, control probands and their families (total sample n=1,750), we conducted three tests of association with CD and 10 SNPs (single nucleotide polymorphisms) in the OXTR gene: (1) family-based comparison utilizing the entire sample; (2) within-Whites, case-control comparison of adolescent patients with CD and controls without CD; and (3) within-Whites case-control comparison of parents of patients and parents of controls.
Family-based association tests failed to show significant results (no results p<0.05). While strictly correcting for the number of tests (α=0.002), adolescent patients with CD did not differ significantly from adolescent controls in genotype frequency for the OXTR SNPs tested; similarly, comparison of OXTR genotype frequencies for parents failed to differentiate patient and control family type, except a trend association for rs237889 (p=0.004).
In this sample, 10 SNPs in the OXTR gene were not significantly associated with CD.
PMCID: PMC3337143  PMID: 21934640
antisocial; delinquency; callousness; genetics
24.  DCDC2 Genetic Variants and Susceptibility to Developmental Dyslexia 
Psychiatric genetics  2012;22(1):25-30.
Developmental Dyslexia is a heritable condition, with genetic factors accounting for 44%–75% of the variance in performance tests of reading component subphenotypes. Compelling genetic linkage and association evidence supports a quantitative trait locus in the 6p21.3 region, which encodes a gene called DCDC2. In the present study, we explored the contribution of two DCDC2 markers to dyslexia, related reading and memory phenotypes in nuclear families of Italian origin.
303 nuclear families recruited on the basis of having a proband with Developmental Dyslexia have been studied with 6p21.3 markers, BV677278 and rs793862. Marker-trait association was investigated by the quantitative transmission disequilibrium test (QTDT, version 2.5.1) as modelled by Abecasis et al. (2000), which allows for the analyses of quantitative traits. Seven phenotypes were used in association analyses, i.e. word and non-word reading, word and non-word spelling, orthographic choice, memory and the affected status based on inclusion criteria.
QTDT analyses yielded evidence for association between reading skills and the BV677278 deletion (empirical p-values= .025–.029) and between memory and BV677278 allele 10 (empirical p-value= .0001).
Our result adds further evidence in support of DCDC2 contributing to the deficits in Developmental Dyslexia. More specifically, our data support the view that DCDC2 influences both reading and memory impairments thus shedding further light into the etiologic basis and the phenotypic complexity of Developmental Dyslexia.
PMCID: PMC3232293  PMID: 21881542
DCDC2; Developmental Dyslexia; Transmission Disequilibrium Test; association study
25.  Interaction between Tryptophan Hydroxylase I (TPH1) Polymorphisms and Childhood Abuse is Associated with Increased Risk for Borderline Personality Disorder in Adulthood 
Psychiatric genetics  2012;22(1):15-24.
Borderline personality disorder (BPD) is a severe disorder with high morbidity and mortality, but unknown etiology. Childhood abuse has been proposed as an etiological factor, but the mechanism by which an abuse history could influence risk for BPD has not been determined. The aim of this study was to determine whether the Tryptophan Hydroxylase 1 gene is related to BPD in a clinical sample, and whether TPH1 genotypes or haplotypes moderate the relationship between abuse history and BPD.
Three hundred ninety-eight patients diagnosed with mood disorders were genotyped for TPH1 G-6526A promoter polymorphism (rs4537731) and the A218C intron 7 polymorphism (rs1800532) and a set of ancestry informative markers, assessed for DSM IV diagnoses, and assessed for a history of physical and/or sexual abuse.
Patients with a diagnosis of BPD were more likely to be risk allele carriers (A alleles at both loci) than the non-BPD group. Logistic regression analysis predicting BPD diagnosis with both single SNPs and haplotypes showed significant interaction effects between genotype and abuse history. Poisson regression predicting the number of BPD diagnostic criteria met with the same predictor set also included a significant interaction term. Risk allele carriers with a history of abuse had an increased likelihood of a BPD diagnosis.
Variation in TPH1may increase risk for developing BPD as a result of childhood abuse. Elements of BPD pathology may be due in part to a genetically influenced serotonergic dysfunction, which in turn may lead to a differential response to environmental stressors.
PMCID: PMC3241896  PMID: 21989108
TPH1; tryptophan hydroxylase; A218C; G-6526A; Borderline Personality Disorder; Childhood Abuse; Suicide; Impulsivity; Impulsiveness

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