Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome-wide SNP (~2.5 million) and gene-based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546 to 1 338; maximum total n=6 268) whose mean age ranged from 55 to 79 years. Meta-analysis of the cohort results was performed, with follow-up associations of the top SNPs and genes investigated in independent cohorts (n=527 to 6 032). Suggestive association (P=8×10−8) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P<6.09×10−6) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene-based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P<0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits.
GWAS; extraversion; neuroticism; anxiety; depression
Methionine sulfoxide reductase (MSRA) is an antioxidant enzyme implicated in protection against oxidative stress and protein maintenance. We have previously reported the association of marker D8S542, located within the MSRA gene, with schizophrenia in the Central Valley of Costa Rica (CVCR). By performing fine mapping analysis, we have now identified a potential 3-marker at risk haplotype within MSRA in the same CVCR sample, with a global P value slightly above nominal significance (P = 0.0526). By sequencing the MSRA gene in individuals carrying this haplotype, we identified a novel four-base pair deletion 1792 bases upstream of the MSRA transcription start site. This deletion was significantly under-transmitted to schizophrenia patients in the CVCR sample (P = 0.0292) using FBAT, and this was replicated in a large independent sample of 321 schizophrenia families from the Hispanic population (P = 0.0367). These findings suggest a protective effect of the deletion against schizophrenia. Further, MSRA mRNA levels were significantly lower in lymphoblastoid cell lines of individuals homozygous for the deletion compared to carriers of the normal allele (P = 0.0135), although significance was only evident when genotypes were collapsed. This suggests that the deleted sequence may play a role in regulating MSRA expression. In conclusion, this work points towards MSRA as a novel schizophrenia candidate gene. Further studies into the mechanisms by which MSRA is involved in schizophrenia pathophysiology may shed light into the biological underpinnings of this disorder.
linkage disequilibrium; Central Valley of Costa Rica; deletion variant; protection; under-transmission
First-degree relatives of persons with bipolar disorders (BD) carry elevated risk for the illness, and manifest deficits in attention and memory (possible “endophenotypes”). However, there is only one published fMRI study of candidate endophenotypes in BD. We used functional magnetic resonance imaging (fMRI) to examine brain function in BD and in first-degree relatives performing a 2-back working memory (WM) task, and correlated brain activity with mood measures taken at the scanning session.
Subjects (age 32–46) were 19 persons with BD, 18 unmedicated, non-psychotic first-degree relatives (RELs) of persons with BD, and 19 matched controls, ascertained from a long-term follow-up of a prenatal cohort study in New England. fMRI signal during 2-back and 0-back WM tasks was measured on a Siemens 1.5T MR scanner. fMRI data were analyzed using SPM-2.
Persons with BD and RELs failed to suppress activation in the left anterior insula (BA 13) during WM, whereas controls suppressed activation. Compared to controls, RELs also failed to suppress activation in the orbitofrontal cortex (OFC) and superior parietal cortex. Controls and RELs exhibited greater activation than BD individuals in the left frontopolar cortex (BA10) during WM. Results remained significant after controlling for confounders except for mild attenuation of OFC findings. Significant correlations between brain activity, mood and WM suggest that activity in WM circuits is affected by activity in emotion-regulatory circuits.
Persons with BD, and RELs exhibit altered activity in the frontopolar cortex and insula, which may represent biomarkers of genetic risk for BD.
bipolar disorder; genetics; functional MRI; working memory; insula; frontopolar cortex
The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. Candidate gene studies have implicated genetic susceptibility loci within immune-related genes; however, these have not been reliably validated. Here we employed genome-wide association (GWA) methods to discover novel genetic susceptibility loci associated with HAND, and validate susceptibility loci implicated in prior candidate gene studies.
Data from 1287 participants enrolled in the Multicenter AIDS Cohort Study between 1985 and 2010 were used. Genotyping was conducted with Illumina 1M, 1MDuo, or 550K platform. Linear mixed models determined subject-specific slopes for change over time in processing speed and executive functioning, considering all visits including baseline and the most recent study visit. Covariates modeled as fixed effects included: time since the first visit, depression severity, nadir CD4+ T-cell count, Hepatitis C co-infection, substance use, and antiretroviral medication regimen. Prevalence of HIV-associated dementia (HAD) and neurocognitive impairment (NCI) was also examined as neurocognitive phenotypes in a case-control analysis.
No genetic susceptibility loci were associated with decline in processing speed or executive functioning among almost 2.5 million single nucleotide polymorphisms (SNPs) directly genotyped or imputed. No association between the SNPs and HAD or NCI were found. Previously reported associations between specific genetic susceptibility loci, HIV-associated neurocognitive impairment and HAD were not validated.
In this first GWAS of HAND, no novel or previously identified genetic susceptibility loci were associated with any of the phenotypes examined. Due to the relatively small sample size, future collaborative efforts that incorporate this dataset may still yield important findings.
HIV; NeuroAIDS; HIV-associated neurocognitive disorder; genome-wide association; HIV-associated dementia
We reported that the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) moderates the effect of childhood adversity on posttraumatic stress disorder (PTSD)risk (Xie and others 2009). In the present study, we considered 5178 subjects (a group with generally high substance dependence comorbidity, as for our previous study) using similar methodology to replicate our previous results.
We used logistic regression analyses to explore the interaction effect of 5-HTTLPR genotype and childhood adversity on PTSD risk. We found that, as reported in our previous study, in individuals with childhood adversity, the presence of one or two copies of the S allele of 5-HTTLPR increased the risk to develop PTSD. This gene-environment interaction effect was present in European Americans (EAs), but not in African Americans (AAs) (EAs, OR=1.49, 95% CI=1.07–2.08, P=0.019; AAs, OR=0.90, 95% CI=0.60–1.35, P=0.62). The statistical power to detect this interaction effect was increased when data were combined with those from our previous study (Xie and others 2009).
The findings reported here replicate those from our previous work, adding to a growing body of research demonstrating that the 5-HTTLPR genotype moderates risk for anxiety and depression phenotypes in the context of stress and adverse events.
gene-environment interaction; PTSD; childhood adversity; 5-HTTLPR
Substantial phenotypic overlap exists between fragile X syndrome (FXS) and autism, suggesting that FMR1 (the gene causing FXS) poses a significant risk for autism. Cross-population comparisons of FXS and autism therefore offer a potentially valuable method for refining the range of phenotypes associated with variation in FMR1. This study adopted a broader phenotype approach, focusing on parents who are at increased genetic liability for autism or FXS. Women who were carriers of FMR1 in its premutation state were compared with mothers of individuals with autism, and controls in an attempt to determine whether subtle features of the broad autism phenotype may express at elevated rates among FMR1 premutation carriers.
The principal personality and language features comprising the broad autism phenotype (i.e., rigid and aloof personality, and particular patterns of pragmatic language use) were assessed among 49 premutation carriers who were mothers of individuals with FXS, 89 mothers of individuals with autism, and 23 mothers of typically developing individuals.
Relative to controls, the autism and premutation parent groups showed elevated rates of certain personality and language characteristics which have been described as constituting the broad autism phenotype.
Findings suggest partially overlapping personality and language profiles among autism and premutation parent groups, with rigid personality style and patterns of pragmatic language use emerging as features most clearly shared between groups. These results provide further evidence for the overlap of autism and FXS, and may implicate FMR1 in some of the subtle features comprising the broad autism phenotype.
Autism; fragile X syndrome; fragile X premutation; FMR1; language; broad autism phenotype
There is a need to collect psychiatric family history information quickly and economically (e.g., for genome-wide studies and primary care practice). We sought to evaluate the validity of family history reports using a brief screening instrument, the Family History Screen (FHS). We assessed the validity of parents’ reports of seven psychiatric disorders in their adult children probands from the Dunedin Study (n=959, 52% male), using the proband’s diagnosis as the criterion outcome. We also investigated whether there were informant characteristics that enhanced accuracy of reporting or were associated with reporting biases. Using reports from multiple informants, we obtained sensitivities ranging from 31.7% (alcohol dependence) to 60.0% (conduct disorder) and specificities ranging from 76.0% (major depressive episode) to 97.1% (suicide attempt). There was little evidence that any informant characteristics enhanced accuracy of reporting. However, three reporting biases were found: the probability of reporting disorder in the proband was greater for informants with versus without a disorder, for female versus male informants, and for younger versus older informants. We conclude that the FHS is as valid as other family history instruments (e.g., the FH-RDC, FISC), and its brief administration time makes it a cost-effective method for collecting family history data. To avoid biasing results, researchers who aim to compare groups in terms of their family history should ensure that the informants reporting on these groups do not differ in terms of age, sex or personal history of disorder.
family history; sensitivity; specificity; accuracy; bias
CHRNA4, the gene that encodes the nicotinic
acetylcholine receptor α4 subunit, is a potential candidate
gene for nicotine dependence (ND). However, studies of the association of
CHNRA4 with smoking behavior have shown inconsistent
results. Our meta-analysis of linkage studies of smoking behavior identified a
genome-wide significant linkage of the phenotype maximum number of cigarettes
smoked in a 24-hour period to a region (20q13.12-q13.32) harboring
CHRNA4. This motivated us to examine the association of
CHRNA4 with smoking behavior in two independent samples. In
this study, we examined five single nucleotide polymorphisms (SNPs) within
CHRNA4 and three smoking-related behaviors: one
quantitative trait [cigarettes smoked per day (CPD)], and two
binary traits [DSM-IV diagnosis of ND and dichotomized Fagerstrom test
of ND (FTND)], in 1,249 unrelated European-Americans (EAs) and 1,790
unrelated African-Americans (AAs). Using the combined sample with sex, age and
race as covariates, the synonymous SNP rs1044394 was significantly associated
with ND (P = 0.001) and FTND (P
= 0.01). Rs2236196, which has a low correlation with rs1044394, was also
significantly associated with CPD (P = 0.003). The
pattern of association for these SNPs was similar in AAs and EAs. After
correction for multiple testing, the association between rs1044394 and ND in the
combined sample remained significant (P = 0.033). In
summary, our study supports association between CHRNA4 common
variation and ND in AA and EA samples. Additional studies will be necessary to
evaluate the role of rare variants at CHRNA4 for ND.
smoking behavior; nicotine dependence; FTND; SNP; association
Autism is a heritable neurodevelopmental disorder with substantial genetic heterogeneity. Studies point to possible links between autism and two serotonin related genes: SLC6A4 and ITGB3 with a sex-specific genetic effect and interaction between the genes. Despite positive findings, inconsistent results have complicated interpretation. This study seeks to validate and clarify previous findings in an independent dataset taking into account sex, family-history (FH) and gene-gene effects. Family-based association analysis was performed within each gene. Gene-gene interactions were tested using extended multifactor dimensionality reduction (EMDR) and MDR-phenomics using sex of affecteds and FH as covariates. No significant associations with individual SNPs were found in the datasets stratified by sex, but associations did emerge when we stratified by family history. While not significant in the overall dataset, nominally significant association was identified at RS2066713 (p=0.006) within SLC6A4 in FH− (family-history negative) families, at RS2066713 (p=0.038) in FH+ (family-history positive) families but with the opposite risk allele as in the FH− families. For ITGB3, nominally significant association was identified at RS3809865 overall (p= 0.040) and within FH+ families (p=0.031). However, none of the association survived the multiple testing corrections. MDR-phenomics confirmed gene-gene effects using sex of affecteds (p=0.023) and family history (p=0.014, survived the multiple testing corrections) as covariates. Our results indicate the extensive heterogeneity within these two genes among families. The potential interaction between SLC6A4 and ITGB3, particularly family history as a promising indicator of genetic architecture further illustrates the importance of covariates as markers of heterogeneity into genetic analyses.
Association; interaction; SLC6A4; ITGB3
The primary goal of this study was to calculate the prevalence of the premutation of the FMR1 gene and of the “gray zone” using a population-based sample of older adults in Wisconsin (n=6,747 samples screened). Compared with past research, prevalence was relatively high (1 in 151 females and 1 in 468 males for the premutation and 1 in 35 females and 1 in 42 males for the gray zone as defined by 45–54 CGG repeats). A secondary study goal was to describe characteristics of individuals found to have the premutation (n = 30, 7 males and 23 females). We found that premutation carriers had a significantly higher rate of divorce than controls, as well as higher rates of symptoms that might be indicative of fragile X-associated tremor ataxia syndrome (FXTAS; numbness, dizziness/faintness) and fragile X primary ovarian insufficiency (FXPOI; age at last menstrual period). Although not statistically significant, premutation carriers were twice as likely to have a child with disability.
FMR1 premutationand gray zoneCGG expansions; prevalence
Previously, we established that short-term T lymphocyte cultures from people with Down syndrome (DS) and dementia (Alzheimer’s Disease) had shorter telomeres than did those from age- and sex- matched people with Down syndrome only, quantified as significantly reduced numbers of signals of PNA telomere probes in whole metaphases [Jenkins et al., 2008] as well as reduced telomere probe light intensity values in interphases [Jenkins et al., 2010]. We now describe shorter telomere length in adults with DS and mild cognitive impairment (MCI) compared to age- and sex-matched individuals with DS without MCI. Telomere length is quantified by reduced telomere signal numbers and shorter chromosome 1 telomeres measured in micrometers (microns). These findings were in agreement with quantitative light intensity measurements of chromosome 1 and chromosome 21 PNA telomere probes with and without the use of a “normalizing ratio” involving the fluorescence exhibited by a PNA probe for centromere 2, and with the use of light intensity measurements of interphase preparations. Most importantly, the distributions of chromosome 1 telomere lengths (in microns) were completely non-overlapping for adults with and without MCI, indicating that this measure has great promise as a biomarker for MCI as well as dementia in this population.
Down Syndrome; Mild Cognitive Impairment; FISH; PNA telomere signal number; Telomere Length in Microns
Covault et al. (2007) reported that the common functional polymorphism, 5-HTTLPR, in the serotonin transporter gene moderated the association between past-year stressful events and daily reports of drinking in a sample of European-American (EA) college students. We examined this effect in college students of African descent.
Students recruited at a Historically Black University (n=564) completed web-based measures of past-year stressful life experiences and daily reports of drinking and heavy drinking over a 30-day period. Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism and dichotomized as low-activity S’ allele carriers or high-activity L’ homozygotes. Generalized linear models were used to examine the effects of life stress, genotype, and their interaction on the two drinking measures.
In students who completed 15 or more daily surveys (n=393), there was a significant interaction of past-year stressful events, 5-HTTLPR genotype, and gender on the number of drinking days (p=0.002). Similar findings were obtained in relation to heavy drinking days (p=0.007). Men showed a main effect of past-year stressful events on both drinking outcomes (p’s<0.001), but no main or moderator effects of genotype. In women, the S’ allele moderated the impact of past-year life stressors on the frequency of drinking and heavy drinking days (p’s<0.001).
In college students of African descent, past-year stressful events were associated with more frequent drinking and heavy drinking, an effect that was moderated by the 5-HTTLPR polymorphism. However, in contrast to the findings in EA students, in the current sample, 5-HTTLPR moderated the association only among women.
gene-environment interaction; college student drinking; alcohol; 5-HTTLPR; daily reports
The fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat in the 5′-untranslated region of exon 1. Once unstable, this repeat is capable of expansion across generations. Women who carry a premutation allele (55–199 repeats) are at risk of passing on a full mutation allele (>200 repeats) to their offspring. A full mutation leads to the most common form of inherited intellectual disability, fragile X syndrome (FXS). Mounting evidence suggests that premutation carriers may be vulnerable to symptoms of anxiety and depression. The goal of this study was to test the hypothesis that among women who carry a premutation, the stress of raising a child with FXS would be moderated by genetic factors influencing endogenous cortisol responses, which could in turn modulate anxiety and depression symptoms. To this end, we genotyped single nucleotide polymorphisms (SNPs) at the corticotrophin releasing hormone receptor 1 locus (CRHR1) in 460 women. Participants completed self-report questionnaires assessing symptoms of depression [Centers for Epidemiological Studies Depression Scale (CESD)], anxiety [State-Trait Anxiety Inventory (STAI) and Social Phobia and Anxiety Inventory (SPAI)], and mood [Positive and Negative Affect Schedule (PANAS)]. Results indicate a statistically significant interaction between CRHR1 genotype and the status of raising a child with FXS to predict social anxiety symptoms reported on the SPAI (rs7209436, P = 0.0001). Our data suggest that genetic variants in CRHR1 that associate with differential cortisol activation may also modulate levels of anxiety related to the stress of raising a child with FXS among women who carry an FMR1 premutation.
FMR1 premutation; fragile X syndrome; hypothalamic-pituitary-adrenal axis; cortisol; gene–environment interaction
Prior work using lymphoblast DNA prepared from 192 subjects from the Iowa Adoption Studies (IAS) demonstrated that decreased MAOA promoter methylation was associated with lifetime symptom count for Nicotine Dependence (ND) and provided suggestive evidence that the amount of methylation is genotype dependent. In the current investigation, we replicate and extend these prior findings in three ways using another 289 IAS subjects and the same methodologies. First, we show that methylation is dependent on current smoking status. Second, we introduce a factor analytic approach to DNA methylation, highlighting three distinct regions of the promoter that may function in somewhat different ways for males and females. Third, we directly compare the methylation signatures in DNA prepared from whole blood and lymphoblasts from a subset of these subjects and provide suggestive evidence favoring the use of lymphoblast DNA. We conclude that smoking reliably decreases MAOA methylation, but exact characterization of effects on level of methylation depend on genotype, smoking history, current smoking status, gender, and region of the promoter-associated CpG Island examined.
Prior studies suggest that obsessive-compulsive symptoms (OCS) and disorder (OCD) are comorbid with dystonia. We tested if OCS/OCD is a clinical manifestation of the DYT1 dystonia mutation by interviewing members of families with an identified DYT1 mutation, and classifying by manifesting carriers (MC), non-manifesting carriers (NMC), and non-carriers (NC). We found that OCD/OCS are not increased in DYT1 mutation carriers compared with NC, nor is OCD associated with manifesting DYT1 dystonia.
dystonia; obsessive-compulsive disorder; psychiatric manifestations; variable expressivity; pleiotropy
In recent years, the role of epigenetic phenomenon, such as methylation, in mediating vulnerability to behavioral illness has become increasingly appreciated. One prominent locus at which epigenetic phenomena are thought to be in play is the Monoamine Oxidase A (MAOA) locus. In order to examine the role of methylation at this locus, we performed quantitative methylation analysis across the promoter region of this gene in lymphoblast lines derived from 191 subjects participating in the Iowa Adoption Studies (IAS). We analyzed the resulting data with respect to genotype and lifetime symptom counts for the more common major behavioral disorders in the IAS, antisocial personality disorder (ASPD), and substance use disorders (alcohol (AD) and nicotine dependence (ND)). We found that methylation status was significantly associated with lifetime symptom counts for ND (p<0.001) and AD (p<0.008) in women, but not men. Furthermore, a trend was found for women homozygous for the 3,3 allele to have a higher degree of overall methylation than women homozygous for the 4,4 allele (p<0.10). We conclude that methylation of MAOA may play a significant role in common psychiatric illness and that further examination of epigenetic processes at this locus is in order.
Using data from the National Institutes of Neurological disease and Stroke's (NINDS) study of Parkinson disease (PD), we recently reported that single nucleotide polymorphisms (SNPs) in a region containing the Calpastatin (CAST) gene were associated with PD. Here we follow up this finding with an analysis of the Center for Inherited Disease Research's (CIDR) genome-wide association study in familial PD. After adjusting for population stratification and multiple testing, we find a significant association (p=0.0167) between PD and SNP rs1559085 in CAST. These findings confirm CAST/PD associations in a second, independent, dataset and suggest that CAST be prioritized for further investigation.
Nail-Patella syndrome (NPS) is an autosomal dominant disorder that is the result of heterozygous loss-of-function mutations in LMX1B, coding for a LIM homeobox (LIM-HD) transcription factor. Analyses of lmx1b mutant mice have revealed the role of Lmx1b in the development of mesencephalic dopaminergic neurons and the serotonergic system; these areas have been linked with symptoms of attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). Fifty adults (38 females, 12 males) with NPS completed the Conners’ Adult ADHD Rating Scales—Self-report: Long Version (CAARS) and Beck Depression Inventory-II (BDI-II). The objective was to describe the neurobehavioral phenotype of these subjects and examine possible relationships between neurobehavioral symptoms and NPS. Elevated levels of DSM-IV-TR ADHD Inattentive symptoms were reported on the CAARS by 22% of the NPS sample. The BDI-II Total score was elevated for 40% of the NPS sample. There was a significant increase in the odds of an elevated BDI-II Total score when any of the three CAARS scales were elevated (odds ratios ranging from 11.455 to 15.615). The CAARS and BDI-II did not significantly differ with gender, age, or education level. There was no significant association between genetic mutation-predicted protein status and elevations on CAARS or BDI-II. Individuals with NPS reported co-occurring symptoms of ADHD and MDD, with higher levels of co-occurrence than reported in the literature for the general population. The co-occurrence of these symptoms may be related to mesencephalic dopaminergic neurologic pathway abnormalities that are a consequence of LMX1B loss of function.
ADHD; MDD; behavior phenotype; neurobehavior
The present study searched for replicable risk genomic regions for alcohol and nicotine co-dependence using a genome-wide association strategy. The data contained a total of 3,143 subjects including 818 European-American (EA) cases with alcohol and nicotine co-dependence, 1,396 EA controls, 449 African-American (AA) cases and 480 AA controls. We performed separate genome-wide association analyses in EAs and AAs and a meta-analysis to derive combined p values, and calculated the genome-wide false discovery rate (FDR) for each SNP. Regions with p<5×10-7 together with FDR<0.05 in the meta-analysis were examined to detect all replicable risk SNPs across EAs, AAs and meta-analysis. These SNPs were followed with a series of functional expression quantitative trait locus (eQTL) analyses. We found a unique genome-wide significant gene region – SH3BP5-NR2C2 – that was enriched with 11 replicable risk SNPs for alcohol and nicotine co-dependence. The distributions of -log(p) values for all SNP-disease associations within this region were consistent across EAs, AAs, and meta-analysis (0.315≤r≤0.868; 8.1×10-52≤p≤3.6×10-5). In the meta-analysis, this region was the only association peak throughout chromosome 3 at p<0.0001. All replicable risk markers available for eQTL analysis had nominal cis- and trans-acting regulatory effects on gene expression. The transcript expression of the genes in this region was regulated partly by several nicotine dependence-related genes and significantly correlated with transcript expression of many alcohol and nicotine dependence-related genes. We concluded that the SH3BP5-NR2C2 region on Chromosome 3 might harbor causal loci for alcohol and nicotine co-dependence.
GWAS; alcohol and nicotine co-dependence
The identification of autism susceptibility genes has been hampered by phenotypic heterogeneity of autism, among other factors. However, the use of endophenotypes has shown preliminary success in reducing heterogeneity and identifying potential autism-related susceptibility regions. To further explore the utility of using language related endophenotypes, we performed linkage analysis on multiplex autism families stratified according to delayed expressive speech and also assessed the extent to which parental phenotype information would aid in identifying regions of linkage. A whole genome scan using a multipoint nonparametric linkage approach was performed in 133 families, stratifying the sample by phrase speech delay and word delay. None of the regions reached suggested genome-wide or replication significance thresholds. However, several loci on chromosomes 1, 2, 4, 6, 7, 8, 9, 10, 12, 15, and 19 yielded nominally higher linkage signals in the delayed groups. The results did not support reported linkage findings for loci on chromosomes 7 or 13 that were a result of stratification based on the language delay endophenotype. In addition, inclusion of information on parental history of language delay did not appreciably affect the linkage results. The nominal increase in NPL scores across several regions using language delay endophenotypes for stratification suggests that this strategy may be useful in attenuating heterogeneity. However, the inconsistencies in regions identified across studies highlight the importance of increasing sample sizes to provide adequate power to test replications in independent samples.
Autism; linkage; endophenotypes; language; AGRE
Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5′ and 3′ regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
FYN; PPP2R4; MAPT; AD; CSF