Imperial College London

Dr. Anna C. Need

Faculty of MedicineDepartment of Medicine

Lecturer in Neuropsychiatric Genetics
 
 
 
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Contact

 

+44 (0)20 3313 8436a.need Website

 
 
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Location

 

7N2aCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

51 results found

Lam M, Trampush JW, Yu J, Knowles E, Davies G, Liewald DC, Starr JM, Djurovic S, Melle I, Sundet K, Christoforou A, Reinvang I, DeRosse P, Lundervold AJ, Steen VM, Espeseth T, Räikkönen K, Widen E, Palotie A, Eriksson JG, Giegling I, Konte B, Roussos P, Giakoumaki S, Burdick KE, Payton A, Ollier W, Chiba-Falek O, Attix DK, Need AC, Cirulli ET, Voineskos AN, Stefanis NC, Avramopoulos D, Hatzimanolis A, Arking DE, Smyrnis N, Bilder RM, Freimer NA, Cannon TD, London E, Poldrack RA, Sabb FW, Congdon E, Conley ED, Scult MA, Dickinson D, Straub RE, Donohoe G, Morris D, Corvin A, Gill M, Hariri AR, Weinberger DR, Pendleton N, Bitsios P, Rujescu D, Lahti J, Le Hellard S, Keller MC, Andreassen OA, Deary IJ, Glahn DC, Malhotra AK, Lencz Tet al., 2017, Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets., Cell Rep, Vol: 21, Pages: 2597-2613

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

JOURNAL ARTICLE

Need AC, Shashi V, Schoch K, Petrovski S, Goldstein DBet al., 2017, The importance of dynamic re-analysis in diagnostic whole exome sequencing, JOURNAL OF MEDICAL GENETICS, Vol: 54, Pages: 155-156, ISSN: 0022-2593

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Trampush JW, Yang MLZ, Yu J, Knowles E, Davies G, Liewald DC, Starr JM, Djurovic S, Melle I, Sundet K, Christoforou A, Reinvang I, DeRosse P, Lundervold AJ, Steen VM, Espeseth T, Raikkonen K, Widen E, Palotie A, Eriksson JG, Giegling I, Konte B, Roussos P, Giakoumaki S, Burdick KE, Payton A, Ollier W, Horan M, Chiba-Falek O, Attix DK, Need AC, Cirulli ET, Voineskos AN, Stefanis NC, Avramopoulos D, Hatzimanolis A, Arking DE, Smyrnis N, Bilder RM, Freimer NA, Cannon TD, London E, Poldrack RA, Sabb FW, Congdon E, Conley ED, Scult MA, Dickinson D, Straub RE, Donohoe G, Morris D, Corvin A, Gill M, Hariri AR, Weinberger DR, Pendleton N, Bitsios P, Rujescu D, Lahti J, Le Hellard S, Keller MC, Andreassen OA, Deary IJ, Glahn DC, Malhotra AK, Lencz Tet al., 2017, GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium, MOLECULAR PSYCHIATRY, Vol: 22, Pages: 336-345, ISSN: 1359-4184

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Trampush JW, Yang MLZ, Yu J, Knowles E, Davies G, Liewald DC, Starr JM, Djurovic S, Melle I, Sundet K, Christoforou A, Reinvang I, DeRosse P, Lundervold AJ, Steen VM, Espeseth T, Raikkonen K, Widen E, Palotie A, Eriksson JG, Giegling I, Konte B, Roussos P, Giakoumaki S, Burdick KE, Payton A, Ollier W, Horan M, Chiba-Falek O, Attix DK, Need AC, Cirulli ET, Voineskos AN, Stefanis NC, Avramopoulos D, Hatzimanolis A, Arking DE, Smyrnis N, Bilder RM, Freimer NA, Cannon TD, London E, Poldrack RA, Sabb FW, Congdon E, Conley ED, Scult MA, Dickinson D, Straub RE, Donohoe G, Morris D, Corvin A, Gill M, Hariri AR, Weinberger DR, Pendleton N, Bitsios P, Rujescu D, Lahti J, Le Hellard S, Keller MC, Andreassen OA, Deary IJ, Glahn DC, Malhotra AK, Lencz Tet al., 2017, GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium (vol 22, pg 336, 2017), MOLECULAR PSYCHIATRY, Vol: 22, Pages: 1651-1652, ISSN: 1359-4184

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Need AC, Goldstein DB, 2016, Neuropsychiatric genomics in precision medicine: diagnostics, gene discovery, and translation, DIALOGUES IN CLINICAL NEUROSCIENCE, Vol: 18, Pages: 237-252, ISSN: 1294-8322

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Shashi V, Pena LDM, Kim K, Burton B, Hempel M, Schoch K, Walkiewicz M, McLaughlin HM, Cho M, Stong N, Hickey SE, Shuss CM, Freemark MS, Bellet JS, Keels MA, Bonner MJ, El-Dairi M, Butler M, Kranz PG, Stumpel CTRM, Klinkenberg S, Oberndorff K, Alawi M, Santer R, Petrovski S, Kuismin O, Korpi-Heikkila S, Pietilainen O, Aarno P, Kurki MI, Hoischen A, Need AC, Goldstein DB, Kortuem Fet al., 2016, De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 99, Pages: 991-999, ISSN: 0002-9297

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Shashi V, Xie P, Schoch K, Goldstein DB, Howard TD, Berry MN, Schwartz CE, Cronin K, Sliwa S, Allen A, Need ACet al., 2015, The RBMX gene as a candidate for the Shashi X-linked intellectual disability syndrome, CLINICAL GENETICS, Vol: 88, Pages: 386-390, ISSN: 0009-9163

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Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu Y-F, McSweeney KM, Ben-Zeev B, Nissenkorn A, Anikster Y, Oz-Levi D, Dhindsa RS, Hitomi Y, Schoch K, Spillmann RC, Heimer G, Marek-Yagel D, Tzadok M, Han Y, Worley G, Goldstein J, Jiang Y-H, Lancet D, Pras E, Shashi V, McHale D, Need AC, Goldstein DBet al., 2015, Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios, Genetics in Medicine, Vol: 17, Pages: 774-781, ISSN: 1530-0366

Purpose:Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations.Methods:We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients.Results:We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes.Conclusion:This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.

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Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, Crimian R, Schoch K, Platt J, Cox R, Bernstein JA, Scavina M, Walter RS, Bibb A, Jones M, Hegde M, Graham BH, Need AC, Oviedo A, Schaaf CP, Boyle S, Butte AJ, Chen R, Clark MJ, Haraksingh R, Cowan TM, He P, Langlois S, Zoghbi HY, Snyder M, Gibbs RA, Freeze HH, Goldstein DBet al., 2014, Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway, GENETICS IN MEDICINE, Vol: 16, Pages: 751-758, ISSN: 1098-3600

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Need AC, Goldstein DB, 2014, Schizophrenia Genetics Comes of Age, NEURON, Vol: 83, Pages: 760-763, ISSN: 0896-6273

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Nutt DJ, Need AC, 2014, Where now for schizophrenia research?, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 24, Pages: 1181-1187, ISSN: 0924-977X

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Shashi V, McConkie-Rosell A, Rosell B, Schoch K, Vellore K, McDonald M, Jiang Y-H, Xie P, Need A, Goldstein DBet al., 2014, The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders, Genetics in Medicine, Vol: 16, Pages: 176-182, ISSN: 1098-3600

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Tiwari AK, Need AC, Lohoff FW, Zai CC, Chowdhury NI, Mueller DJ, Putkonen A, Repo-Tiihonen E, Hallikainen T, Yagcioglu AEA, Tiihonen J, Kennedy JL, Meltzer HYet al., 2014, Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis, MOLECULAR PSYCHIATRY, Vol: 19, Pages: 403-405, ISSN: 1359-4184

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Zhu X, Need AC, Petrovski S, Goldstein DBet al., 2014, One gene, many neuropsychiatric disorders: lessons from Mendelian diseases, NATURE NEUROSCIENCE, Vol: 17, Pages: 773-781, ISSN: 1097-6256

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Smith PJ, Need AC, Cirulli ET, Chiba-Falek O, Attix DKet al., 2013, A comparison of the Cambridge Automated Neuropsychological Test Battery (CANTAB) with "traditional" neuropsychological testing instruments, JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY, Vol: 35, Pages: 319-328, ISSN: 1380-3395

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Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, Need AC, Ge D, He M, Cirulli ET, Zhao Q, Cronin KD, Gumbs CE, Campbell CR, Hong LK, Maia JM, Shianna KV, McCormack M, Radtke RA, O'Conner GD, Mikati MA, Gallentine WB, Husain AM, Sinha SR, Chinthapalli K, Puranam RS, McNamara JO, Ottman R, Sisodiya SM, Delanty N, Goldstein DBet al., 2012, Exome Sequencing Followed by Large-Scale Genotyping Fails to Identify Single Rare Variants of Large Effect in Idiopathic Generalized Epilepsy, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 293-302, ISSN: 0002-9297

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Need AC, McEvoy JP, Gennarelli M, Heinzen EL, Ge D, Maia JM, Shianna KV, He M, Cirulli ET, Gumbs CE, Zhao Q, Campbell CR, Hong L, Rosenquist P, Putkonen A, Hallikainen T, Repo-Tiihonen E, Tiihonen J, Levy DL, Meltzer HY, Goldstein DBet al., 2012, Exome Sequencing Followed by Large-Scale Genotyping Suggests a Limited Role for Moderately Rare Risk Factors of Strong Effect in Schizophrenia, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 303-312, ISSN: 0002-9297

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Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, Goldstein DBet al., 2012, Clinical application of exome sequencing in undiagnosed genetic conditions, JOURNAL OF MEDICAL GENETICS, Vol: 49, Pages: 353-361, ISSN: 0022-2593

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Zhu M, Need AC, Han Y, Ge D, Maia JM, Zhu Q, Heinzen EL, Cirulli ET, Pelak K, He M, Ruzzo EK, Gumbs C, Singh A, Feng S, Shianna KV, Goldstein DBet al., 2012, Using ERDS to Infer Copy-Number Variants in High-Coverage Genomes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 408-421, ISSN: 0002-9297

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Dennis NA, Cabeza R, Need AC, Waters-Metenier S, Goldstein DB, LaBar KSet al., 2011, Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Hippocampal Activation During Episodic Encoding and Retrieval Tasks, HIPPOCAMPUS, Vol: 21, Pages: 980-989, ISSN: 1050-9631

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Ge D, Ruzzo EK, Shianna KV, He M, Pelak K, Heinzen EL, Need AC, Cirulli ET, Maia JM, Dickson SP, Zhu M, Singh A, Allen AS, Goldstein DBet al., 2011, SVA: software for annotating and visualizing sequenced human genomes, BIOINFORMATICS, Vol: 27, Pages: 1998-2000, ISSN: 1367-4803

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Pelak K, Need AC, Fellay J, Shianna KV, Feng S, Urban TJ, Ge D, De Luca A, Martinez-Picado J, Wolinsky SM, Martinson JJ, Jamieson BD, Bream JH, Martin MP, Borrow P, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Carrington M, Goldstein DB, Alter Get al., 2011, Copy Number Variation of KIR Genes Influences HIV-1 Control, PLOS BIOLOGY, Vol: 9, ISSN: 1544-9173

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Cirulli ET, Kasperaviciute D, Attix DK, Need AC, Ge D, Gibson G, Goldstein DBet al., 2010, Common genetic variation and performance on standardized cognitive tests, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 18, Pages: 815-819, ISSN: 1018-4813

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Cirulli ET, Kasperaviit D, Attix DK, Need AC, Ge D, Gibson G, Goldstein DBet al., 2010, Erratum: Common genetic variation and performance on standardized cognitive tests (European Journal of Human Genetics (2010) 18 (820) DOI: 10.1038/ejhg.2010.2), European Journal of Human Genetics, Vol: 18, ISSN: 1018-4813

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Dennis NA, Browndyke JN, Stokes J, Need A, Burke JR, Welsh-Bohmer KA, Cabeza Ret al., 2010, Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers., Alzheimers Dement, Vol: 6, Pages: 303-311

BACKGROUND: We sought to determine if the APOE epsilon4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTLs) during successful memory encoding in young adults. METHODS: Twenty-four healthy young adults, i.e., 12 carriers and 12 noncarriers of the APOE epsilon4 allele, were scanned in a subsequent-memory paradigm, using event-related functional magnetic resonance imaging. The neuroanatomic correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTLs, as well as whole-brain functional connectivity with the MTLs, were assessed. RESULTS: In the absence of demographic or performance differences, APOE epsilon4 allele carriers exhibited greater bilateral MTL activity relative to noncarriers while accomplishing the same encoding task. Moreover, whereas epsilon4 carriers demonstrated a greater functional connectivity of ESA-related MTL activity with the posterior cingulate and other peri-limbic regions, reductions in overall connectivity were found across the anterior and posterior cortices. CONCLUSIONS: These results suggest that the APOE varepsilon4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTLs to other regions implicated in memory encoding. Enhanced functional connectivity of the MTLs with the posterior cingulate in young adult epsilon4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer's disease, long before late-onset dementia is a practical risk or consideration. These functional connectivity differences may also reflect pleiotropic effects of APOE during early development.

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Dennis NA, Need AC, LaBar KS, Waters-Metenier S, Cirulli ET, Kragel J, Goldstein DB, Cabeza Ret al., 2010, COMT Val(108/158) Met Genotype Affects Neural but not Cognitive Processing in Healthy Individuals, CEREBRAL CORTEX, Vol: 20, Pages: 672-683, ISSN: 1047-3211

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Heinzen EL, Need AC, Hayden KM, Chiba-Falek O, Roses AD, Strittmatter WJ, Burke JR, Hulette CM, Welsh-Bohmer KA, Goldstein DBet al., 2010, Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer's Disease, JOURNAL OF ALZHEIMERS DISEASE, Vol: 19, Pages: 69-77, ISSN: 1387-2877

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Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciute D, Tate SK, Caboclo LO, Sander JW, Clayton L, Linney KN, Shianna KV, Gumbs CE, Smith J, Cronin KD, Maia JM, Doherty CP, Pandolfo M, Leppert D, Middleton LT, Gibson RA, Johnson MR, Matthews PM, Hosford D, Kalviainen R, Eriksson K, Kantanen A-M, Dorn T, Hansen J, Kraemer G, Steinhoff BJ, Wieser H-G, Zumsteg D, Ortega M, Wood NW, Huxley-Jones J, Mikati M, Gallentine WB, Husain AM, Buckley PG, Stallings RL, Podgoreanu MV, Delanty N, Sisodiya SM, Goldstein DBet al., 2010, Rare Deletions at 16p13.11 Predispose to a Diverse Spectrum of Sporadic Epilepsy Syndromes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 86, Pages: 707-718, ISSN: 0002-9297

JOURNAL ARTICLE

Need AC, Goldstein DB, 2010, Whole genome association studies in complex diseases: where do we stand?, Dialogues Clin Neurosci, Vol: 12, Pages: 37-46, ISSN: 1294-8322

Hundreds of genome-wide association studies have been performed in recent years in order to try to identify common variants that associate with complex disease. These have met with varying success. Some of the strongest effects of common variants have been found in late-onset diseases and in drug response. The major histocompatibility complex has also shown very strong association with a variety of disorders. Although there have been some notable success stories in neuropsychiatric genetics, on the whole, common variation has explained little of the high heritability of these traits. In contrast, early studies of rare copy number variants have led rapidly to a number of genes and loci that strongly associate with neuropsychiatric disorders. It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance our understanding of neuropsychiatric genetics.

JOURNAL ARTICLE

Need AC, Goldstein DB, 2010, Whole genome association studies in complex diseases: Where do we stand?, Dialogues in Clinical Neuroscience, Vol: 12, Pages: 34-43, ISSN: 1294-8322

Hundreds of genome-wide association studies have been performed in recent years in order to try to identify common variants that associate with complex disease. These have met with varying success. Some of the strongest effects of common variants have been found in late-onset diseases and in drug response. The major histo-compatibility complex has also shown very strong association with a variety of disorders. Although there have been some notable success stories in neuropsychiatric genetics, on the whole, common variation has explained little of the high heritability of these traits. In contrast, early studies of rare copy number variants have led rapidly to a number of genes and loci that strongly associate with neuropsychiatric disorders. It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance our understanding of neuropsychiatric genetics. © 2010, LLS SAS. All rights reserved.

JOURNAL ARTICLE

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