Publications by authors named "Denise Harold"

53 Publications

Rare Copy Number Variants Are Associated With Poorer Cognition in Schizophrenia.

Biol Psychiatry 2020 Dec 19. Epub 2020 Dec 19.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address:

Background: Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia.

Methods: General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment.

Results: A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = -0.66, 95% confidence interval [CI] = -1.31 to -0.01) and replication samples (β = -0.91, 95% CI = -1.71 to -0.11) and after meta-analysis (β = -0.76, 95% CI = -1.26 to -0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = -0.15, 95% CI = -0.29 to -0.001, p = .048).

Conclusions: In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.025DOI Listing
December 2020

A review of pharmaceutical occurrence and pathways in the aquatic environment in the context of a changing climate and the COVID-19 pandemic.

Anal Methods 2021 02 28;13(5):575-594. Epub 2021 Jan 28.

DCU Water Institute, School of Chemical Sciences, Dublin City University, Glasnevin, Dublin 9, Ireland.

Active pharmaceutical ingredients (APIs) are increasingly being identified as contaminants of emerging concern (CECs). They have potentially detrimental ecological and human health impacts but most are not currently subject to environmental regulation. Addressing the life cycle of these pharmaceuticals plays a significant role in identifying the potential sources and understanding the environmental impact that pharmaceuticals may have in surface waters. The stability and biological activity of these "micro-pollutants" can lead to a pseudo persistence, with ensuing unknown chronic behavioural and health-related effects. Research that investigates pharmaceuticals predominantly focuses on their occurrence and effect within surface water environments. However, this review will help to collate this information with factors that affect their environmental concentration. This review focuses on six pharmaceuticals (clarithromycin, ciprofloxacin, sulfamethoxazole, venlafaxine, gemfibrozil and diclofenac), chosen because they are heavily consumed globally, have poor removal rates in conventional activated sludge wastewater treatment plants (CAS WWTPs), and are persistent in the aquatic environment. Furthermore, these pharmaceuticals are included in numerous published prioritisation studies and/or are on the Water Framework Directive (WFD) "Watch List" or are candidates for the updated Watch List (WL). This review investigates the concentrations seen in European Union (EU) surface waters and examines factors that influence final concentrations prior to release, thus giving a holistic overview on the source of pharmaceutical surface water pollution. A period of 10 years is covered by this review, which includes research from 2009-2020 examining over 100 published studies, and highlighting that pharmaceuticals can pose a severe risk to surface water environments, with each stage of the lifecycle of the pharmaceutical determining its concentration. This review additionally highlights the necessity to improve education surrounding appropriate use, disposal and waste management of pharmaceuticals, while implementing a source directed and end of pipe approach to reduce pharmaceutical occurrence in surface waters.
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http://dx.doi.org/10.1039/d0ay02098bDOI Listing
February 2021

The Differential Influence of Immune, Endocytotic, and Lipid Metabolism Genes on Amyloid Deposition and Neurodegeneration in Subjects at Risk of Alzheimer's Disease.

J Alzheimers Dis 2021 ;79(1):127-139

Imperial College London, London, United Kingdom.

Background: Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects.

Objective: The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls.

Methods: AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes.

Results: Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism.

Conclusion: Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.
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http://dx.doi.org/10.3233/JAD-200578DOI Listing
January 2021

Effects of complement gene-set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls.

Am J Med Genet B Neuropsychiatr Genet 2020 12 12;183(8):445-453. Epub 2020 Sep 12.

Cognitive Genetics & Cognitive Therapy Group, The Centre for Neuroimaging, Cognition and Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant. A post-hoc analysis of hippocampal subfields suggested an association between complement PRS and several hippocampal subfields, findings that appeared to be particularly driven by the patient sample. In conclusion, our study yielded suggestive evidence of association between complement-based schizophrenia PRS and variation in memory function and hippocampal volume.
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http://dx.doi.org/10.1002/ajmg.b.32820DOI Listing
December 2020

Identifying schizophrenia patients who carry pathogenic genetic copy number variants using standard clinical assessment: retrospective cohort study.

Br J Psychiatry 2020 05;216(5):275-279

Professor, Head of Discipline, Neuropsychiatric Genetics Research Group, Department of Psychiatry, School of Medicine, Trinity College Dublin, Ireland.

Background: Copy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia.

Aims: To determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort.

Method: Logistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479).

Results: In the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16-34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58-14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28-19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9-86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0-100.0%) for the replication cohort.

Conclusions: These findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.
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http://dx.doi.org/10.1192/bjp.2019.262DOI Listing
May 2020

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls.

Genes Brain Behav 2019 11 30;18(8):e12602. Epub 2019 Aug 30.

Cognitive Genetics & Cognitive Therapy Group, The Center for Neuroimaging, Cognition and Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune-relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene-set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene-set was enriched for genes associated with human intelligence and SZ risk, using genome-wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene-set analysis with a complement gene-set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene-based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome-wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.
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http://dx.doi.org/10.1111/gbb.12602DOI Listing
November 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

Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia.

Am J Med Genet B Neuropsychiatr Genet 2019 04 23;180(3):223-231. Epub 2019 Feb 23.

Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition & Genomics (NICOG) Centre & NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.
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http://dx.doi.org/10.1002/ajmg.b.32716DOI Listing
April 2019

Analysis of shared heritability in common disorders of the brain.

Science 2018 06;360(6395)

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
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http://dx.doi.org/10.1126/science.aap8757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097237PMC
June 2018

Effects of MiR-137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls.

Am J Med Genet B Neuropsychiatr Genet 2018 04 8;177(3):369-376. Epub 2018 Feb 8.

The Cognitive Genetics & Cognitive Therapy Group, The School of Psychology and Discipline of Biochemistry, The Centre for Neuroimaging & Cognitive Genomics, National University of Ireland Galway, Galway, Ireland.

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R  = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure.
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http://dx.doi.org/10.1002/ajmg.b.32620DOI Listing
April 2018

A modifier of Huntington's disease onset at the MLH1 locus.

Hum Mol Genet 2017 10;26(19):3859-3867

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets.
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http://dx.doi.org/10.1093/hmg/ddx286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455020PMC
October 2017

Haplotype-based stratification of Huntington's disease.

Eur J Hum Genet 2017 11 23;25(11):1202-1209. Epub 2017 Aug 23.

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD.
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http://dx.doi.org/10.1038/ejhg.2017.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643960PMC
November 2017

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

Cognitive Characterization of Schizophrenia Risk Variants Involved in Synaptic Transmission: Evidence of CACNA1C's Role in Working Memory.

Neuropsychopharmacology 2017 Dec 13;42(13):2612-2622. Epub 2017 Jun 13.

The Cognitive Genetics & Cognitive Therapy Group, The School of Psychology and Discipline of Biochemistry, The Centre for Neuroimaging & Cognitive Genomics, National University of Ireland Galway, Galway, Ireland.

With >100 common variants associated with schizophrenia risk, establishing their biological significance is a priority. We sought to establish cognitive effects of risk variants at loci implicated in synaptic transmission by (1) identifying GWAS schizophrenia variants whose associated gene function is related to synaptic transmission, and (2) testing for association between these and measures of neurocognitive function. We selected variants, reported in the largest GWAS to date, associated with genes involved in synaptic transmission. Associations between genotype and cognitive test score were analyzed in a discovery sample (988 Irish participants, including 798 with psychosis), and replication samples (528 UK patients with schizophrenia/schizoaffective disorder; 921 German participants including 362 patients with schizophrenia). Three loci showed significant associations with neuropsychological performance in the discovery samples. This included an association between the rs2007044 (risk allele G) within CACNA1C and poorer working memory performance (increased errors B (95% CI)=0.635-4.535, p=0.012), an effect driven mainly by the psychosis groups. In an fMRI analysis of working memory performance (n=84 healthy participants, a subset of the discovery sample), we further found evidence that the same CACNA1C allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and right superior occipital gyrus/cuneus and anterior cingulate cortex. In conclusion, these data provide evidence to suggest that the CACNA1C risk variant rs2007044 is associated with poorer memory function that may result from risk carriers' difficulty with top-down initiated responses caused by dysconnectivity between the right DLPFC and several cortical regions.
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http://dx.doi.org/10.1038/npp.2017.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686488PMC
December 2017

Cognitive analysis of schizophrenia risk genes that function as epigenetic regulators of gene expression.

Am J Med Genet B Neuropsychiatr Genet 2016 12 20;171(8):1170-1179. Epub 2016 Oct 20.

Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics (NICOG) Centre and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression, to orchestrate brain development, adult neurogenesis, and synaptic plasticity. These processes when perturbed are thought to contribute to schizophrenia pathophysiology. A core feature of schizophrenia is cognitive dysfunction. For genetic disorders where cognitive impairment is more severe such as intellectual disability, there are a disproportionally high number of genes involved in the epigenetic regulation of gene transcription. Evidence now supports some shared genetic aetiology between schizophrenia and intellectual disability. GWAS have identified 108 chromosomal regions associated with schizophrenia risk that span 350 genes. This study identified genes mapping to those loci that have epigenetic functions, and tested the risk alleles defining those loci for association with cognitive deficits. We developed a list of 350 genes with epigenetic functions and cross-referenced this with the GWAS loci. This identified eight candidate genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE, SATB2. Using a dataset of Irish psychosis cases and controls (n = 1235), the schizophrenia risk SNPs at these loci were tested for effects on IQ, working memory, episodic memory, and attention. Strongest associations were for rs6984242 with both measures of IQ (P = 0.001) and episodic memory (P = 0.007). We link rs6984242 to CHD7 via a long range eQTL. These associations were not replicated in independent samples. Our study highlights that a number of genes mapping to risk loci for schizophrenia may function as epigenetic regulators of gene expression but further studies are required to establish a role for these genes in cognition. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32503DOI Listing
December 2016

Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.

Ann Neurol 2016 05 23;79(5):739-747. Epub 2016 Feb 23.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Objective: Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic Stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.

Methods: Using genome wide association study (GWAS) data from METASTROKE+ (15,916 IS cases and 68,826 controls) and IGAP (17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets to identify the SNPs and molecular pathways through which disease risk may be conferred.

Results: We found evidence of a shared genetic contribution between AD and small vessel stroke (rG(SE)=0.37(0.17); p=0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall, or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE+ small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1), associated with both diseases (p=1.8x10 ). A pathway analysis identified four associated pathways, involving cholesterol transport and immune response.

Interpretation: Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.24621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864940PMC
May 2016

Common polygenic variation enhances risk prediction for Alzheimer's disease.

Brain 2015 Dec 21;138(Pt 12):3673-84. Epub 2015 Oct 21.

1 Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK

The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.
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http://dx.doi.org/10.1093/brain/awv268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006219PMC
December 2015

The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease.

J Huntingtons Dis 2015 ;4(3):279-84

Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.

Background: Huntington's disease (HD) is a dominantly inherited disease caused by a CAG expansion mutation in HTT. The age at onset of clinical symptoms is determined primarily by the length of this CAG expansion but is also influenced by other genetic and/or environmental factors.

Objective: Recently, through genome-wide association studies (GWAS) aimed at discovering genetic modifiers, we identified loci associated with age at onset of motor signs that are significant at the genome-wide level. However, many additional HD modifiers may exist but may not have achieved statistical significance due to limited power.

Methods: In order to disseminate broadly the entire GWAS results and make them available to complement alternative approaches, we have developed the internet website "GeM MOA" where genetic association results can be searched by gene name, SNP ID, or genomic coordinates of a region of interest.

Results: Users of the Genetic Modifiers of Motor Onset Age (GeM MOA) site can therefore examine support for association between any gene region and age at onset of HD motor signs. GeM MOA's interactive interface also allows users to navigate the surrounding region and to obtain association p-values for individual SNPs.

Conclusions: Our website conveys a comprehensive view of the genetic landscape of modifiers of HD from the existing GWAS, and will provide the means to evaluate the potential influence of genes of interest on the onset of HD. GeM MOA is freely available at https://www.hdinhd.org/.
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http://dx.doi.org/10.3233/JHD-150169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753529PMC
July 2016

Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?

J Nucl Med 2015 May 3;56(5):707-13. Epub 2015 Apr 3.

Neurology Imaging Unit, Imperial College London, Hammersmith Campus, London, United Kingdom MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom; and

Unlabelled: Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded by the rs6971 single-nucleotide polymorphism, with a 40%-50% increase in BP in high-affinity binders (HABs) compared with mixed-affinity binders (MABs), whereas low-affinity binders (LABs) are unsuitable for evaluation. Hence, several studies are using either HAB alone or HAB and MAB subjects. To translate the findings of neuroinflammation studies to the entire population, it is crucial to establish the influence of TSPO genotypes on AD. Here, we investigated whether different TSPO genotypes influence cognitive function, amyloid load, and disease progression over time.

Methods: We evaluated 798 subjects (225 control, 388 with mild cognitive impairment [MCI], and 185 with AD) from the Alzheimer's Disease Neuroimaging Initiative database at baseline and during follow-up. All subjects were screened for TSPO genotype and underwent detailed clinical and neuropsychologic assessments yearly for 4 y. Of the 798 subjects, 255 also had T1- and T2-weighted MR imaging and amyloid PET with (11)C-Pittsburgh compound B or (18)F-florbetapir.

Results: We demonstrated that all TSPO binding groups (HAB, MAB, and LAB) have same level of amyloid load in AD and MCI subjects. We also demonstrated that the prevalence is 50.3% for HAB, 41.2% for MAB, and 8.5% for LAB, without a statistical difference among the AD, MCI, and control groups. During longitudinal follow-up, the mean change in neuropsychometric test scores on the Mini-Mental State Examination, the cognitive and modified Alzheimer Disease Assessment Scales (ADASs), and the Geriatric Depression Scale over time were similar in AD and MCI subjects among the 3 TSPO binding groups. Analysis of the covariates showed that diagnostic group (control, MCI, AD), apolipoprotein E4 status, and sex had a significant effect on decline on the modified Alzheimer Disease Assessment Scale (>3 points of the scale), but age and TSPO genotype did not.

Conclusion: This study suggests that information obtained from evaluating a subgroup of AD or MCI subject using second-generation TSPO tracers can be translated to the entire AD and MCI population. Thus, we can study fewer AD subjects in evaluating new antineuroinflammatory and antimicroglial agents in intervention studies and in observational studies evaluating the role of neuroinflammation.
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http://dx.doi.org/10.2967/jnumed.114.149443DOI Listing
May 2015

Erratum to "Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome" [Neurobiol. Aging 35 (2014) 1513.e1-1513.e5].

Neurobiol Aging 2014 Nov 17;35(11):2659. Epub 2014 Jul 17.

Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK; Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; The London Down Syndrome (LonDownS) Consortium, UK.

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http://dx.doi.org/10.1016/j.neurobiolaging.2014.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617742PMC
November 2014

Genome-wide association interaction analysis for Alzheimer's disease.

Neurobiol Aging 2014 Nov 28;35(11):2436-2443. Epub 2014 May 28.

Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Belgium.

We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = -0.19, p = 0.0006) and cerebellum (β = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370231PMC
November 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

Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome.

Neurobiol Aging 2014 Jun 27;35(6):1513.e1-5. Epub 2013 Dec 27.

Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK; Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; The London Down Syndrome (LonDownS) Consortium, UK.

It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969241PMC
June 2014

Missense variant in TREML2 protects against Alzheimer's disease.

Neurobiol Aging 2014 Jun 21;35(6):1510.e19-26. Epub 2013 Dec 21.

Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.

TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961557PMC
June 2014

Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.

JAMA Neurol 2013 Oct;70(10):1268-76

Importance: Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders.

Objective: To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD.

Design: Combined GWA analysis.

Setting: Data sets from the United Kingdom, Germany, France, and the United States.

Participants: Thousands of patients with AD or PD and their controls.

Main Outcomes And Measures: Meta-analysis of GWA studies of AD and PD.

Methods: To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD.

Results: Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD.

Conclusions And Relevance: Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.
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http://dx.doi.org/10.1001/jamaneurol.2013.448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978422PMC
October 2013

Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome.

Neurobiol Aging 2013 Oct 18;34(10):2441.e1-5. Epub 2013 Apr 18.

Wolfson Centre for Age-Related Diseases, King's College London, London, UK.

It is known that individuals with Down syndrome develop Alzheimer's disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer's disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer's disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer's disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer's disease in Down syndrome.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898582PMC
October 2013