Anna C Need

Publications of Anna C Need

• Clinical application of exome sequencing in undiagnosed genetic conditions.

  Authors: Anna C Need, Vandana Shashi, Yuki Hitomi, Kelly Schoch, Kevin V Shianna, Marie T McDonald, Miriam H Meisler, David B Goldstein

  Journal of medical genetics. 05/2012;

  BackgroundThere is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinicalBackgroundThere is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.MethodsThe authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.ResultsThis undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features).ConclusionsThis study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.

• Correction: Copy Number Variation of KIR Genes Influences HIV-1 Control.

  Authors: Kimberly Pelak, Anna C Need, Jacques Fellay, Kevin V Shianna, Sheng Feng, Thomas J Urban, Dongliang Ge, Andrea De Luca, Javier Martinez-Picado, Steven M Wolinsky [......] Jay H Bream, Maureen P Martin, Persephone Borrow, Norman L Letvin, Andrew J McMichael, Barton F Haynes, Amalio Telenti, Mary Carrington, David B Goldstein, Galit Alter

  PLoS biology. 12/2011; 9(12).

  [This corrects the article on p. e1001208 in vol. 9.].

• Copy number variation of KIR genes influences HIV-1 control.

  Authors: Kimberly Pelak, Anna C Need, Jacques Fellay, Kevin V Shianna, Sheng Feng, Thomas J Urban, Dongliang Ge, Andrea De Luca, Javier Martinez-Picado, Steven M Wolinsky [......] Jay H Bream, Maureen P Martin, Persephone Borrow, Norman L Letvin, Andrew J McMichael, Barton F Haynes, Amalio Telenti, Mary Carrington, David B Goldstein, Galit Alter

  PLoS biology. 11/2011; 9(11):e1001208.

  A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control asA genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.

• SVA: software for annotating and visualizing sequenced human genomes.

  Authors: Dongliang Ge, Elizabeth K Ruzzo, Kevin V Shianna, Min He, Kimberly Pelak, Erin L Heinzen, Anna C Need, Elizabeth T Cirulli, Jessica M Maia, Samuel P Dickson, Mingfu Zhu, Abanish Singh, Andrew S Allen, David B Goldstein

  Bioinformatics (Oxford, England). 05/2011; 27(14):1998-2000.

  SUMMARY: Here we present Sequence Variant Analyzer (SVA), a software tool that assigns a predicted biological function to variants identified in next-generation sequencing studies and provides aSUMMARY: Here we present Sequence Variant Analyzer (SVA), a software tool that assigns a predicted biological function to variants identified in next-generation sequencing studies and provides a browser to visualize the variants in their genomic contexts. SVA also provides for flexible interaction with software implementing variant association tests allowing users to consider both the bioinformatic annotation of identified variants and the strength of their associations with studied traits. We illustrate the annotation features of SVA using two simple examples of sequenced genomes that harbor Mendelian mutations. Availability and implementation: Freely available on the web at http://www.svaproject.org.

• The characterization of twenty sequenced human genomes.

  Authors: Kimberly Pelak, Kevin V Shianna, Dongliang Ge, Jessica M Maia, Mingfu Zhu, Jason P Smith, Elizabeth T Cirulli, Jacques Fellay, Samuel P Dickson, Curtis E Gumbs [......] Linda K Hong, Katharina A Lornsen, Alexander M McKenzie, Nara L M Sobreira, Julie E Hoover-Fong, Joshua D Milner, Ruth Ottman, Barton F Haynes, James J Goedert, David B Goldstein

  PLoS genetics. 09/2010; 6(9).

  We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case"We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.

• Common genetic variation and performance on standardized cognitive tests.

  Authors: Elizabeth T Cirulli, Dalia Kasperaviciūte, Deborah K Attix, Anna C Need, Dongliang Ge, Greg Gibson, David B Goldstein

  European journal of human genetics : EJHG. 07/2010; 18(7):815-20.

  One surprising feature of the recently completed waves of genome-wide association studies is the limited impact of common genetic variation in individually detectable polymorphisms on many humanOne surprising feature of the recently completed waves of genome-wide association studies is the limited impact of common genetic variation in individually detectable polymorphisms on many human traits. This has been particularly pronounced for studies on psychiatric conditions, which have failed to produce clear, replicable associations for common variants. One popular explanation for these negative findings is that many of these traits may be genetically heterogeneous, leading to the idea that relevant endophenotypes may be more genetically tractable. Aspects of cognition may be the most important endophenotypes for psychiatric conditions such as schizophrenia, leading many researchers to pursue large-scale studies on the genetic contributors of cognitive performance in the normal population as a surrogate for aspects of liability to disease. Here, we perform a genome-wide association study with two tests of executive function, Digit Symbol and Stroop Color-Word, in 1086 healthy volunteers and with an expanded cognitive battery in 514 of these volunteers. We show that, consistent with published studies of the psychiatric conditions themselves, no single common variant has a large effect (explaining >4-8% of the population variation) on the performance of healthy individuals on standardized cognitive tests. Given that these are important endophenotypes, our work is consistent with the idea that identifying rare genetic causes of psychiatric conditions may be more important for future research than identifying genetically homogenous endophenotypes.

• Brain-derived neurotrophic factor val66met polymorphism and hippocampal activation during episodic encoding and retrieval tasks.

  Authors: Nancy A Dennis, Roberto Cabeza, Anna C Need, Sheena Waters-Metenier, David B Goldstein, Kevin S Labar

  Hippocampus. 05/2010;

  Brain-derived neurotrophic factor (BDNF) is a neurotrophin which has been shown to regulate cell survival and proliferation, as well as synaptic growth and hippocampal long-term potentiation. ABrain-derived neurotrophic factor (BDNF) is a neurotrophin which has been shown to regulate cell survival and proliferation, as well as synaptic growth and hippocampal long-term potentiation. A naturally occurring single nucleotide polymorphism in the human BDNF gene (val66met) has been associated with altered intercellular trafficking and regulated secretion of BDNF in met compared to val carriers. Additionally, previous studies have found a relationship between the BDNF val66met genotype and functional activity in the hippocampus during episodic and working memory tasks in healthy young adults. Specifically, studies have found that met carriers exhibit both poorer performance and reduced neural activity within the medial temporal lobe (MTL) when performing episodic memory tasks. However, these studies have not been well replicated and have not considered the role of behavioral differences in the interpretation of neural differences. The current study sought to control for cognitive performance in investigating the role of the BDNF val66met genotype on neural activity associated with episodic memory. Across item and relational memory tests, met carriers exhibited increased MTL activation during both encoding and retrieval stages, compared to noncarriers. The results suggest that met carriers are able to recruit MTL activity to support successful memory processes, and reductions in cognitive performance observed in prior studies are not a ubiquitous effect associated with variants of the BDNF val66met genotype. © 2010 Wiley-Liss, Inc.

• Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

  Authors: Erin L Heinzen, Rodney A Radtke, Thomas J Urban, Gianpiero L Cavalleri, Chantal Depondt, Anna C Need, Nicole M Walley, Paola Nicoletti, Dongliang Ge, Claudia B Catarino [......] Julie Huxley-Jones, Mohamad Mikati, William B Gallentine, Aatif M Husain, Patrick G Buckley, Ray L Stallings, Mihai V Podgoreanu, Norman Delanty, Sanjay M Sisodiya, David B Goldstein

  American journal of human genetics. 05/2010; 86(5):707-18.

  Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structuralDeletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

• Whole genome association studies in complex diseases: where do we stand?

  Authors: Anna C Need, David B Goldstein

  Dialogues in clinical neuroscience. 01/2010; 12(1):37-46.

  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.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.

• Genome-wide scan of copy number variation in late-onset Alzheimer's disease.

  Authors: Erin L Heinzen, Anna C Need, Kathleen M Hayden, Ornit Chiba-Falek, Allen D Roses, Warren J Strittmatter, James R Burke, Christine M Hulette, Kathleen A Welsh-Bohmer, David B Goldstein

  Journal of Alzheimer's disease : JAD. 01/2010; 19(1):69-77.

  Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide associationAlzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE epsilon4 risk allele, identified a novel variant that influences disease risk within the APOE epsilon4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.

• Next generation disparities in human genomics: concerns and remedies.

  Authors: Anna C Need, David B Goldstein

  Trends in genetics : TIG. 11/2009; 25(11):489-94.

  Studies of human genetics, particularly genome-wide association studies (GWAS), have concentrated heavily on European populations, with individuals of African ancestry rarely represented. Reasons forStudies of human genetics, particularly genome-wide association studies (GWAS), have concentrated heavily on European populations, with individuals of African ancestry rarely represented. Reasons for this include the distribution of biomedical funding and the increased population structure and reduced linkage disequilibrium in African populations. Currently, few GWAS findings have clinical utility and, therefore, the field has not yet contributed to health-care disparities. As human genomics research progresses towards the whole-genome sequencing era, however, more clinically relevant results are likely to be discovered. As we discuss here, to avoid the genetics community contributing to healthcare disparities, it is important to adopt measures to ensure that populations of diverse ancestry are included in genomic studies, and that no major population groups are excluded.

• A Genome-wide Study of Common SNPs and CNVs in Cognitive Performance in the CANTAB battery.

  Authors: Anna C Need, Deborah K Attix, Jill M McEvoy, Elizabeth T Cirulli, Kristen L. Linney, Priscilla Hunt, Dongliang Ge, Erin L Heinzen, Jessica M Maia, Kevin V Shianna, Michael E Weale, Lynn F Cherkas, Gail Clement, Tim D Spector, Greg Gibson, David B Goldstein

  Human molecular genetics. 10/2009;

  Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studyingPsychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the CANTAB battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory (SRM and VRM), we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants (CNVs). Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower-than-expected p values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

• COMT Val108/158 Met Genotype Affects Neural but not Cognitive Processing in Healthy Individuals.

  Authors: Nancy A Dennis, Anna C Need, Kevin S Labar, Sheena Waters-Metenier, Elizabeth T Cirulli, James Kragel, David B Goldstein, Roberto Cabeza

  Cerebral cortex (New York, N.Y. : 1991). 08/2009;

  The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on theThe relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496-1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.

• Common variants conferring risk of schizophrenia.

  Authors: Hreinn Stefansson, Roel A Ophoff, Stacy Steinberg, Ole A Andreassen, Sven Cichon, Dan Rujescu, Thomas Werge, Olli P H Pietiläinen, Ole Mors, Preben B Mortensen [......] David A Collier, René S Kahn, Don H Linszen, Jim van Os, Durk Wiersma, Richard Bruggeman, Wiepke Cahn, Lieuwe de Haan, Lydia Krabbendam, Inez Myin-Germeys

  Nature. 08/2009;

  Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in theSchizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

• A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.

  Authors: Sreekumar G Pillai, Dongliang Ge, Guohua Zhu, Xiangyang Kong, Kevin V Shianna, Anna C Need, Sheng Feng, Craig P Hersh, Per Bakke, Amund Gulsvik, Andreas Ruppert, Karin C Lødrup Carlsen, Allen Roses, Wayne Anderson, Stephen I Rennard, David A Lomas, Edwin K Silverman, David B Goldstein

  PLoS genetics. 04/2009; 5(3):e1000421.

  There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency ofThere is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of alpha(1)-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10), (rs8034191) and 5.74 x 10(-10) (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

• A genome-wide investigation of SNPs and CNVs in schizophrenia.

  Authors: Anna C Need, Dongliang Ge, Michael E Weale, Jessica Maia, Sheng Feng, Erin L Heinzen, Kevin V Shianna, Woohyun Yoon, Dalia Kasperaviciūte, Massimo Gennarelli [......] Gillian Fraser, Caroline Crombie, Lefkos T Middleton, David St Clair, Allen D Roses, Pierandrea Muglia, Clyde Francks, Dan Rujescu, Herbert Y Meltzer, David B Goldstein

  PLoS genetics. 02/2009; 5(2):e1000373.

  We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following upWe report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

• Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis.

  Authors: Anna C Need, Richard Se Keefe, Dongliang Ge, Iris Grossman, Sam Dickson, Joseph P McEvoy, David B Goldstein

  European journal of human genetics : EJHG. 02/2009;

  The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. AlthoughThe Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.European Journal of Human Genetics advance online publication, 21 January 2009; doi:10.1038/ejhg.2008.264.

• Large recurrent microdeletions associated with schizophrenia.

  Authors: Hreinn Stefansson, Dan Rujescu, Sven Cichon, Olli P H Pietiläinen, Andres Ingason, Stacy Steinberg, Ragnheidur Fossdal, Engilbert Sigurdsson, Thordur Sigmundsson, Jacobine E Buizer-Voskamp [......] Kari Stefansson, René S Kahn, Don H Linszen, Jim van Os, Durk Wiersma, Richard Bruggeman, Wiepke Cahn, Lieuwe de Haan, Lydia Krabbendam, Inez Myin-Germeys

  Nature. 10/2008; 455(7210):232-236.

  Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk ofReduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

• Failure to replicate effect of Kibra on human memory in two large cohorts of European origin.

  Authors: Anna C Need, Deborah K Attix, Jill M McEvoy, Elizabeth T Cirulli, Kristen N Linney, Ana Patricia Wagoner, Curtis E Gumbs, Ina Giegling, Hans-Jürgen Möller, Clyde Francks, Pierandrea Muglia, Allen Roses, Greg Gibson, Mike E Weale, Dan Rujescu, David B Goldstein

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 08/2008; 147B(5):667-8.

  It was recently suggested that the Kibra polymorphism rs17070145 has a strong effect on multiple episodic memory tasks in humans. We attempted to replicate this using two cohorts of European geneticIt was recently suggested that the Kibra polymorphism rs17070145 has a strong effect on multiple episodic memory tasks in humans. We attempted to replicate this using two cohorts of European genetic origin (n = 319 and n = 365). We found no association with either the original SNP or a set of tagging SNPs in the Kibra gene with multiple verbal memory tasks, including one that was an exact replication (Auditory Verbal Learning Task, AVLT). These results suggest that Kibra does not have a strong and general effect on human memory.

• Long-range LD can confound genome scans in admixed populations.

  Authors: Alkes L Price, Michael E Weale, Nick Patterson, Simon R Myers, Anna C Need, Kevin V Shianna, Dongliang Ge, Jerome I Rotter, Esther Torres, Kent D Taylor, David B Goldstein, David Reich

  American journal of human genetics. 08/2008; 83(1):132-5; author reply 135-9.