Publications by authors named "Amy Gerrish"

24 Publications

  • Page 1 of 1

The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma.

Cancers (Basel) 2021 Mar 29;13(7). Epub 2021 Mar 29.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.

Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic analysis was only possible if an affected eye was removed as part of a treatment. Several recent proof of principle studies have demonstrated that the analysis of tumour-derived cell-free DNA, either obtained from ocular fluid or blood plasma, has the potential to advance the diagnosis and influence the prognosis of retinoblastoma patients. It has been shown that a confirmed diagnosis is possible in retinoblastoma patients undergoing conservative treatment. In vivo genetic analysis of retinoblastoma tumours is also now possible, allowing the potential identification of secondary genetic events as prognostic biomarkers. In addition, noninvasive prenatal diagnosis in children at risk of inheriting retinoblastoma has been developed. Here, we review the current literature and discuss the potential impact of cell-free DNA analysis on both the diagnosis and treatment of retinoblastoma patients and their families.
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http://dx.doi.org/10.3390/cancers13071570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037190PMC
March 2021

Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies.

J Clin Med 2020 Oct 30;9(11). Epub 2020 Oct 30.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.

Retinoblastoma, the most common childhood eye cancer, presents in two forms: heritable or sporadic. Heritable retinoblastoma is caused by a germline mutation in the gene. Early diagnosis of children at risk of inheriting an mutation is crucial to achieve optimal clinical outcome. Currently, the majority of genetic testing is performed on newborns, which has multiple disadvantages for both families and the healthcare system. We have developed a non-invasive prenatal diagnosis (NIPD) service for retinoblastoma, available from 8 weeks' gestation, which uses a combination of massively parallel sequencing (MPS) techniques, dependent on the inheritance model. Detection of paternal or suspected de novo variants is achieved through amplicon-based MPS. NIPD of a fetus at risk of maternal inheritance is performed using capture-based targeted sequencing and relative haplotype dosage analysis. In addition, we show proof of principle of how capture-based sequencing can be used for de novo variants unsuitable for amplicon-based testing. In total, we report the NIPD of 15 pregnancies, results of which show 100% concordance with all postnatal testing performed at the time of publication ( = 12) with remaining pregnancies ongoing. NIPD of retinoblastoma therefore offers a viable alternative to newborn genetic testing.
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http://dx.doi.org/10.3390/jcm9113517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692133PMC
October 2020

Clinical Service Delivery of Noninvasive Prenatal Diagnosis by Relative Haplotype Dosage for Single-Gene Disorders.

J Mol Diagn 2020 09 15;22(9):1151-1161. Epub 2020 Jun 15.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Edgbaston, United Kingdom.

A relative haplotype dosage (RHDO)-based method was developed and implemented into routine clinical practice for noninvasive prenatal diagnosis (NIPD) of multiple single-gene disorders: spinal muscular atrophy, Duchenne and Becker muscular dystrophies, and cystic fibrosis. This article describes the experiences of the first 152 pregnancies to have NIPD by RHDO as part of a routine clinical service. Provision of results within a clinically useful time frame (mean, 11 calendar days) was shown to be possible, with a very low failure rate (4%), none being due to a technical failure. Where follow-up confirmatory testing was performed for audit purposes, 100% concordance was seen with the NIPD result, and no discrepancies have been reported. The robust performance of the assay, together with high sensitivity and specificity, demonstrates that NIPD by RHDO is feasible for use in a clinical setting.
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http://dx.doi.org/10.1016/j.jmoldx.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471768PMC
September 2020

Peritonsillar abscess in an infant with congenital bone marrow failure.

Int J Pediatr Otorhinolaryngol 2019 Sep 29;124:200-202. Epub 2019 May 29.

Department of Paediatric Otorhinolaryngology, Nottingham Children's Hospital, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK.

Peritonsillar abscess is extremely rare in infants and is potentially life-threatening. We report the case of a 3 month old infant with a background of congenital bone marrow failure who presented with sepsis and desaturation requiring intubation and PICU care. Ultrasound and CT scan revealed an inflammatory mass. Examination in theatre revealed a self-draining quinsy. Following formal drainage in theatre, the child improved and was extubated uneventfully 1 day later. Prompt surgical and medical management as well as the presence of a well-coordinated multidisciplinary team are crucial in ensuring the adequate management of complex paediatric patients.
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http://dx.doi.org/10.1016/j.ijporl.2019.05.037DOI Listing
September 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Non-invasive diagnosis of retinoblastoma using cell-free DNA from aqueous humour.

Br J Ophthalmol 2019 Feb 11. Epub 2019 Feb 11.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

Retinoblastoma is the most common eye malignancy in childhood caused by mutations in the gene. Both alleles of the gene must be mutated for tumour development. The initial mutation may be constitutional germline or somatic (originating in one retinal cell only). Distinguishing between these alternative mechanisms is crucial, with wider implications for management of the patient and family members. Bilateral retinoblastoma is nearly always due to a constitutional mutation; however, approximately 15% of unilateral cases also carry a germline mutation, and identifying these cases is important. This can be achieved by identifying both mutation types in tumour tissue and excluding their presence in blood. Modern eye-saving chemotherapy treatment (systemic, intra-arterial and intravitreal) has resulted in fewer enucleations. As a result, tumour tissue required to identify sporadic mutation(s) is not always available. Modern intravitreal chemotherapeutic techniques for retinoblastoma involve aspiration of aqueous humour (AH), providing a novel sample source for analysis. By analysing cell-free DNA present in the AH fluid of eyes affected with retinoblastoma, we have developed a screening test capable of detecting somatic mutations that is comparable to current tests on enucleated tumour tissue. The results obtained with fluid from enucleated eyes were concordant with tumour tissue in all 10 cases analysed. In addition, AH analysis from two patients undergoing intravitreal chemotherapy successfully identified somatic variants in both cases. Our findings suggest that AH fluid is a promising source of tumour-derived DNA in retinoblastoma for analysis.
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http://dx.doi.org/10.1136/bjophthalmol-2018-313005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709774PMC
February 2019

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Nat Genet 2017 09 17;49(9):1373-1384. Epub 2017 Jul 17.

Boston University School of Medicine, Boston, Massachusetts, USA.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10, odds ratio (OR) = 0.68, minor allele frequency (MAF) = 0.0059, MAF = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10, OR = 1.43, MAF = 0.011, MAF = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10, OR = 1.67, MAF = 0.0143, MAF = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
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http://dx.doi.org/10.1038/ng.3916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669039PMC
September 2017

Hydrocephalus and trigeminal neuralgia: exploring the association and management options.

Br J Neurosurg 2017 Jun 19;31(3):296-299. Epub 2017 Apr 19.

b Department of Neurosurgery , Queen's Medical Centre, Nottingham University Hospitals , Nottingham , UK.

We report the successful surgical management of three patients with trigeminal neuralgia and hydrocephalus. MRI revealed no neurovascular contact at the trigeminal root entry zone. Trigeminal neuralgic symptoms were controlled following alleviation of hydrocephalus. We hypothesize that trigeminal nerve traction, secondary to hydrocephalus, as the cause for their trigeminal neuralgia.
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http://dx.doi.org/10.1080/02688697.2017.1317719DOI Listing
June 2017

Case 239: Cerebrotendinous Xanthomatosis.

Radiology 2017 Mar;282(3):916-921

From the Department of Radiology, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 5WW, England.

History A 63-year-old man with learning difficulties presented to the Accident and Emergency Department with right ankle pain after an inversion injury and underwent plain radiography. The patient had developed normally until his teenage years, at which point he experienced cognitive regression. He experienced swallowing difficulties, tinnitus, and fecal incontinence, and he had undergone cataract surgery at the age of 20 years. He also had a small nodule on the volar surface of his right ring finger. Magnetic resonance (MR) imaging of the brain and the right ankle had been performed 3 years previously. Routine biochemistry (full blood count and renal function) results were normal. Total cholesterol level was 3.6 mmol/L (normal, <5.0 mmol/L). The patient had three siblings who had the same condition, with one having died in childhood.
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http://dx.doi.org/10.1148/radiol.2016150707DOI Listing
March 2017

Case 239.

Radiology 2016 11;281(2):635-638

From the Department of Radiology, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 5WW, England.

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http://dx.doi.org/10.1148/radiol.2016150706DOI Listing
November 2016

Decreasing the expression of PICALM reduces endocytosis and the activity of β-secretase: implications for Alzheimer's disease.

BMC Neurosci 2016 07 18;17(1):50. Epub 2016 Jul 18.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, UK.

Background: Polymorphisms in the gene for phosphatidylinositol binding clathrin assembly protein (PICALM), an endocytic-related protein, are associated with a small, increased risk of developing Alzheimer's disease (AD), strongly suggesting that changes in endocytosis are involved in the aetiology of the disease. We have investigated the involvement of PICALM in the processing of amyloid precursor protein (APP) to understand how PICALM could be linked to the development of AD. We used siRNA to deplete levels of PICALM, its isoforms and clathrin heavy chain in the human brain-derived H4 neuroglioma cell line that expresses endogenous levels of APP. We then used Western blotting, ELISA and immunohistochemistry to detect intra- and extracellular protein levels of endocytic-related proteins, APP and APP metabolites including β-amyloid (Aβ). Levels of functional endocytosis were quantified using ALEXA 488-conjugated transferrin and flow cytometry as a marker of clathrin-mediated endocytosis (CME).

Results: Following depletion of all the isoforms of PICALM by siRNA in H4 cells, levels of intracellular APP, intracellular β-C-terminal fragment (β-CTF) and secreted sAPPβ (APP fragments produced by β-secretase cleavage) were significantly reduced but Aβ40 was not affected. Functional endocytosis was significantly reduced after both PICALM and clathrin depletion, highlighting the importance of PICALM in this process. However, depletion of clathrin did not affect APP but did reduce β-CTF levels. PICALM depletion altered the intracellular distribution of clathrin while clathrin reduction affected the subcellular pattern of PICALM labelling. Both PICALM and clathrin depletion reduced the expression of BACE1 mRNA and PICALM siRNA reduced protein levels. Individual depletion of PICALM isoforms 1 and 2 did not affect APP levels while clathrin depletion had a differential effect on the isoforms, increasing isoform 1 while decreasing isoform 2 expression.

Conclusions: The depletion of PICALM in brain-derived cells has significant effects on the processing of APP, probably by reducing CME. In particular, it affects the production of β-CTF which is increasingly considered to be an important mediator in AD independent of Aβ. Thus a decrease in PICALM expression in the brain could be beneficial to slow or prevent the development of AD.
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http://dx.doi.org/10.1186/s12868-016-0288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949774PMC
July 2016

Brain white matter tracts: functional anatomy and clinical relevance.

Semin Ultrasound CT MR 2014 Oct 24;35(5):432-44. Epub 2014 Jun 24.

Department of Neuroradiology, Queens Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.

Diffusion tensor imaging is increasingly available on clinical magnetic resonance scanners and can be acquired in a relatively short time. There has been an explosion of applications in the research field but the use to the practicing radiologist may seem obscure. This paper aims to highlight how diffusion tensor imaging can be used to prompt a dedicated neuroanatomical search for white matter lesions in clinical presentations relating to motor, sensory, language, and visuospatial deficits. The enhanced depiction of white matter tracts in the temporal stem is also highlighted, which is a region of importance in epilepsy surgery planning.
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http://dx.doi.org/10.1053/j.sult.2014.06.003DOI Listing
October 2014

SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

Hum Mol Genet 2014 Dec 15;23(24):6644-58. Epub 2014 Jul 15.

Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.

Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42.
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http://dx.doi.org/10.1093/hmg/ddu372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240204PMC
December 2014

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

PLoS One 2014 12;9(6):e94661. Epub 2014 Jun 12.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094661PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055488PMC
October 2015

Genetic variation at the CELF1 (CUGBP, elav-like family member 1 gene) locus is genome-wide associated with Alzheimer's disease and obesity.

Am J Med Genet B Neuropsychiatr Genet 2014 Jun 1;165B(4):283-93. Epub 2014 May 1.

Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.

Deviations from normal body weight are observed prior to and after the onset of Alzheimer's disease (AD). Midlife obesity confers increased AD risk in later life, whereas late-life obesity is associated with decreased AD risk. The role of underweight and weight loss for AD risk is controversial. Based on the hypothesis of shared genetic variants for both obesity and AD, we analyzed the variants identified for AD or obesity from genome-wide association meta-analyses of the GERAD (AD, cases = 6,688, controls = 13,685) and GIANT (body mass index [BMI] as measure of obesity, n = 123,865) consortia. Our cross-disorder analysis of genome-wide significant 39 obesity SNPs and 23 AD SNPs in these two large data sets revealed that: (1) The AD SNP rs10838725 (pAD  = 1.1 × 10(-08)) at the locus CELF1 is also genome-wide significant for obesity (pBMI  = 7.35 × 10(-09) ). (2) Four additional AD risk SNPs were nominally associated with obesity (rs17125944 at FERMT2, pBMI  = 4.03 × 10(-05), pBMI corr  = 2.50 × 10(-03) ; rs3851179 at PICALM; pBMI  = 0.002, rs2075650 at TOMM40/APOE, pBMI  = 0.024, rs3865444 at CD33, pBMI  = 0.024). (3) SNPs at two of the obesity risk loci (rs4836133 downstream of ZNF608; pAD  = 0.002 and at rs713586 downstream of RBJ/DNAJC27; pAD  = 0.018) were nominally associated with AD risk. Additionally, among the SNPs used for confirmation in both studies the AD risk allele of rs1858973, with an AD association just below genome-wide significance (pAD  = 7.20 × 10(-07)), was also associated with obesity (SNP at IQCK/GPRC5B; pBMI  = 5.21 × 10(-06) ; pcorr  = 3.24 × 10(-04)). Our first GWAS based cross-disorder analysis for AD and obesity suggests that rs10838725 at the locus CELF1 might be relevant for both disorders.
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http://dx.doi.org/10.1002/ajmg.b.32234DOI Listing
June 2014

GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.

Neuron 2013 Apr 4;78(2):256-68. Epub 2013 Apr 4.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ₄₂ are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻⁹ for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻⁸ and p = 3.22 × 10⁻⁹ for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻⁸ for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻⁴, 0.039, 4.86 × 10⁻⁵, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
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http://dx.doi.org/10.1016/j.neuron.2013.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664945PMC
April 2013

A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.

Hum Mol Genet 2013 Feb 11;22(4):816-24. Epub 2012 Nov 11.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.

We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.
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http://dx.doi.org/10.1093/hmg/dds476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554198PMC
February 2013

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

J Alzheimers Dis 2012 ;28(2):377-87

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
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http://dx.doi.org/10.3233/JAD-2011-110824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118466PMC
May 2012

No evidence that extended tracts of homozygosity are associated with Alzheimer's disease.

Am J Med Genet B Neuropsychiatr Genet 2011 Dec 2;156B(7):764-71. Epub 2011 Aug 2.

MRC Centre for Neuropyschiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Cardiff University, Heath Park.

We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.
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http://dx.doi.org/10.1002/ajmg.b.31216DOI Listing
December 2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Nat Genet 2011 May 3;43(5):429-35. Epub 2011 Apr 3.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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http://dx.doi.org/10.1038/ng.803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084173PMC
May 2011

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

PLoS One 2010 Nov 15;5(11):e13950. Epub 2010 Nov 15.

Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom.

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981526PMC
November 2010

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.

Nat Genet 2009 Oct 6;41(10):1088-93. Epub 2009 Sep 6.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).
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http://dx.doi.org/10.1038/ng.440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845877PMC
October 2009

No evidence for association between polymorphisms in GRM3 and schizophrenia.

BMC Psychiatry 2005 May 13;5:23. Epub 2005 May 13.

Department of Psychological Medicine, Wales School of Medicine, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, UK.

Background: Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3.

Methods: In a bid to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples.

Results: Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns.

Conclusion: Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia.
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http://dx.doi.org/10.1186/1471-244X-5-23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142331PMC
May 2005
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