ORCID Profile
0000-0003-2427-2513
Current Organisation
Nottingham Trent University
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Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.NEULET.2010.03.035
Abstract: Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism s les from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any s le or in a combined s le (n=436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian s les.
Publisher: Wiley
Date: 28-12-2007
DOI: 10.1002/AJMG.B.30659
Abstract: There are conflicting reports suggesting that the parental origin of transmitted risk alleles may play a role in the etiology of attention deficit/hyperactivity disorder (ADHD). A recent report by Hawi and colleagues observed a generalized paternal over-transmission of alleles associated with ADHD. This was not replicated in more recent studies. Using data from a large multicenter study we examined the overall and gene-specific parent of origin effect in 554 independent SNPs across 47 genes. Transmission disequilibrium and explicit parent of origin test were performed using PLINK. Overall parent of origin effect was tested by Chi-square. There was no overall parent of origin effect in the IMAGE s le (chi(1)(2) = 1.82, P = 0.117). Five markers in three genes, DDC, TPH2, and SLC6A2 showed nominal association (P < 0.01) with ADHD combined subtype when restricted to maternal or paternal transmission only. Following the initial report by Hawi and co-workers three studies, including this one, found no evidence to support an overall parent of origin effect for markers associated with ADHD. We cannot however, exclude gene-specific parent of origin effect in the etiology ADHD.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2017
DOI: 10.1038/NG.3916
Publisher: Wiley
Date: 10-2008
Publisher: Wiley
Date: 05-2008
DOI: 10.1002/AJMG.B.30737
Abstract: Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long-allele of a 44-bp insertion/deletion polymorphism (5-HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12-allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a s le of 1,020 families with 1,166 combined type ADHD cases for the International Multi-Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the s le of ADHD cases.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.PNPBP.2010.03.029
Abstract: Some children with ADHD also have social and communication difficulties similar to those seen in children with autistic spectrum disorders and this may be due to shared genetic liability. As the oxytocin receptor (OXTR) gene has been implicated in social cognition and autistic spectrum disorders, this study investigated whether OXTR polymorphisms previously implicated in autism were associated with ADHD and whether they influenced OXTR mRNA expression in 27 normal human amygdala brain s les. The family-based association s le consisted of 450 DSM-IV diagnosed ADHD probands and their parents. Although there was no association with the ADHD phenotype, an association with social cognitive impairments in a subset of the ADHD probands (N=112) was found for SNP rs53576 (F=5.24, p=0.007) with post-hoc tests demonstrating that the AA genotype was associated with better social ability compared to the AG genotype. Additionally, significant association was also found for rs13316193 (F=3.09, p=0.05) with post-hoc tests demonstrating that the CC genotype was significantly associated with poorer social ability than the TT genotype. No significant association between genotype and OXTR mRNA expression was found. This study supports previous evidence that the OXTR gene is implicated in social cognition.
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.NEULET.2009.06.084
Abstract: Genetic associations for Attention Deficit Hyperactivity Disorder (ADHD), a common highly heritable childhood behavioural disorder, require replication in order to establish whether they are true positive findings. The current study aims to replicate recent association findings from the International Multi-centre ADHD Genetics (IMAGE) project in one of the most studied genes related to ADHD, the dopamine transporter (DAT1) gene. In a family-based s le of 450 ADHD probands, three Single Nucleotide Polymorphism (SNP) markers have been genotyped using TaqMan assays. Transmission Disequilibrium Test analysis demonstrates that one of three SNP markers (rs11564750) in the 5' promoter region of the gene is significantly associated with ADHD (P=0.02). This provides further evidence that in addition to the well-known and investigated 3'UTR polymorphism associated with ADHD, there is potentially a further association signal emanating from the 5' promoter region of the gene. Further replication and functional studies are now required to fully understand the consequence of polymorphisms present at both the 5' and 3' ends of the DAT1 gene and their role in ADHD pathophysiology.
Publisher: Elsevier BV
Date: 10-2008
Publisher: American Medical Association (AMA)
Date: 2006
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common heritable childhood behavioral disorder. Identifying risk factors for ADHD may lead to improved intervention and prevention. The dopamine transporter gene (DAT1) is associated with ADHD in several studies, with an average 1.2 odds ratio and evidence of heterogeneity across data sets. To investigate sources of heterogeneity by refining the DAT1 association using additional markers and investigating gene-environment interaction between DAT1 and maternal use of alcohol and tobacco during pregnancy. Prospective study. Children with ADHD from child behavior clinics in the southeast of England and in the Taipei area of Taiwan. Within-family tests of association using 2 repeat polymorphisms in the 3' untranslated region and intron 8 plus additional markers in the English s le. Transmission ratios of risk alleles from heterozygote parents to affected offspring and comparison of the transmission ratios in high- and low-exposure groups for the environmental variables. A novel association was identified between ADHD, the intron 8 polymorphism, and a specific risk haplotype in both English and Taiwanese s les. The risk haplotype showed significant interactions with maternal use of alcohol during pregnancy. The identification of a common haplotype in 2 independent populations is an important step toward identifying functionally significant regions of DAT1. Interaction between DAT1 genotypes and maternal use of alcohol during pregnancy suggests that DAT1 moderates the environmental risk and has implications for the prevention of ADHD. Further studies are required to delineate the precise causal risk factor involved in this interaction.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2008
Abstract: As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13) both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.
Publisher: Springer Science and Business Media LLC
Date: 04-2022
DOI: 10.1038/S41588-022-01024-Z
Abstract: Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Publisher: Elsevier BV
Date: 05-2021
DOI: 10.1016/J.NEUROBIOLAGING.2020.11.009
Abstract: Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the "synaptic PRS" in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%-6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify in iduals at risk of LOAD before symptom onset.
Publisher: Wiley
Date: 22-09-2010
DOI: 10.1002/AJMG.B.31120
Publisher: Wiley
Date: 19-11-2007
DOI: 10.1002/AJMG.B.30596
Abstract: A major goal of genetic studies of attention deficit hyperactivity disorder (ADHD) is to identify in idual characteristics that might help segregate the disorder's inherent heterogeneity. [Mill et al. (2006) Arch Ger Psychiatry 63:462-469] recently reported a potentially important association between two dopamine-related risk polymorphisms (DRD4 variable number tandem repeat (VNTR) in exon 3 and DAT1 VNTR in the 3' UTR) and lowered IQ in ADHD. The objective of the current study was to replicate the [Mill et al. (2006) Arch Ger Psychiatry 63:462-469] findings in a clinical s le and to extend the analysis to a large range of alternative SNP markers of putative ADHD risk alleles identified in a recent study [Brookes et al. (2006) Mol Genet 11:934-953]. Participants were 1081 children and adolescents with a research-confirmed combined type ADHD diagnosis and 1300 unaffected siblings who took part in the International Multi-centre ADHD Genetics (IMAGE) project. They were recruited from multiple settings from across Europe: Belgium, Britain, Germany, Ireland, Israel, Netherlands, Spain and Switzerland. The results were that ADHD was associated with reduced IQ. However, there was no association between the two dopamine-related risk polymorphisms and IQ in either the probands or their siblings. Furthermore, other selected genetic markers previously demonstrated to be associated with ADHD in this s le were not associated with IQ. This large scale study with a clinically ascertained and regorously diagnosed s le failed to replicate the association between genetic polymorphisms in the dopamine system and IQ in ADHD. We also observed no association of other SNPs with IQ in ADHD.
Publisher: Wiley
Date: 24-05-2007
DOI: 10.1002/AJMG.B.30562
Abstract: Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent s les collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD.
Publisher: Wiley
Date: 30-07-2008
DOI: 10.1002/AJMG.B.30782
Abstract: Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 3' end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5' regulatory sequences. In this study we replicate the association of SNPs at the 5' end of the gene and identify a specific risk haplotype spanning the 5' and 3' markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD.
Publisher: Wiley
Date: 20-10-2008
DOI: 10.1002/AJMG.B.30873
Abstract: Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder affecting children worldwide. The male bias in the prevalence of the disorder, suggests that some susceptibility genes may lie on the X chromosome. In this study we present evidence for a role of the X-linked steroid sulfatase (STS) gene and neurosteroids in the development of ADHD. Previously it has been observed that probands with ADHD have lower serum concentrations of the neurosteroids DHEA, which is synthesized from DHEA-S by STS. In further support, boys that suffer from XLI, a skin disorder caused by the deletion of the STS gene, have higher rates of ADHD, in particular the inattentive subtype. In a moderately sized s le of ADHD families (N = 384), we genotyped seven single nucleotide polymorphisms, tagging the entire gene. TDT analysis of the data yielded two polymorphisms that were significantly associated with ADHD (rs2770112-Transmitted: 71 Not Transmitted 48 rs12861247-Transmitted: 43 Not Transmitted: 21), located towards the 5' end of the gene (P < 0.05). We conclude that the STS gene may play a role in susceptibility for ADHD, and that the neurosteroids pathways should be investigated further to access their potential contribution in susceptibility to the disorder.
Publisher: Wiley
Date: 21-12-2009
DOI: 10.1002/AJMG.B.30960
Abstract: We [Hawi et al. (2005) Am J Hum Genet 77:958-965] reported paternal over-transmission of risk alleles in some ADHD-associated genes. This was particularly clear in the case of the DAT1 3'-UTR VNTR. In the current investigation, we analyzed three new s le comprising of 1,248 ADHD nuclear families to examine the allelic over-transmission of DAT1 in ADHD. The IMAGE s le, the largest of the three-replication s les, provides strong support for a parent of origin effect for allele 6 and the 10 repeat allele (intron 8 and 3'-UTR VNTR, respectively) of DAT1. In addition, a similar pattern of over-transmission of paternal risk haplotypes (constructed from the above alleles) was also observed. Some support is also derived from the two smaller s les although neither is independently significant. Although the mechanism driving the paternal over-transmission of the DAT risk alleles is not known, these finding provide further support for this phenomenon.
Publisher: Wiley
Date: 20-10-2008
DOI: 10.1002/AJMG.B.30872
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Keeley Brookes.