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1.  Brain-derived neurotrophic factor Val66Met polymorphism and hippocampal activation during episodic encoding and retrieval tasks 
Hippocampus  2010;21(9):980-989.
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. 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 non-carriers. 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.
doi:10.1002/hipo.20809
PMCID: PMC3010486  PMID: 20865733
2.  Clinical application of exome sequencing in undiagnosed genetic conditions 
Journal of Medical Genetics  2012;49(6):353-361.
Background
There 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.
Methods
The 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.
Results
This 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).
Conclusions
This 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.
doi:10.1136/jmedgenet-2012-100819
PMCID: PMC3375064  PMID: 22581936
Exome sequencing; unidentified genetic conditions; medical genetics; paediatrics; clinical genetics; complex traits; genetic screening/counselling; genetics; genome-wide; psychotic disorders (including schizophrenia); molecular genetics; gastroenterology; immunology (including allergy).
4.  Copy Number Variation of KIR Genes Influences HIV-1 Control 
PLoS Biology  2011;9(11):e1001208.
The authors that the number of activating and inhibitory KIR genes varies between individuals and plays a role in the regulation of immune mechanisms that determine HIV-1 control.
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 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.
Author Summary
There is marked intrinsic variation in the extent to which individuals are able to control HIV-1. We have identified a genetic copy number variable region (CNV) in humans that plays a significant role in the control of HIV-1. This CNV is located in the genomic region that encodes the killer cell immunoglobulin-like receptors (KIRs) and specifically affects the KIR3DS1 and KIR3DL1 genes, encoding two KIRs that interact with human leukocyte antigen B (HLA-B) ligands. KIRs are expressed on the surface of natural killer (NK) cells, which serve as important players in the innate immune response, and are involved in the recognition of infected and malignant cells through a loss or alteration in “self” ligands. We use both genetic association and functional evidence to show a strong interaction between KIR3DL1 and KIR3DS1, indicating that increasing gene counts for KIR3DL1 confer increasing levels of protection against HIV-1, but only in the presence of at least one copy of KIR3DS1. This effect was associated with a dramatic increase in the abundance of KIR3DS1+ NK cells in the peripheral blood, and strongly associated with a more robust capacity of peripheral NK cells to suppress HIV-1 replication in vitro. This work provides one of the few examples of an association between a relatively common CNV and a human complex trait.
doi:10.1371/journal.pbio.1001208
PMCID: PMC3226550  PMID: 22140359
6.  Common genetic variation and performance on standardized cognitive tests 
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 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.
doi:10.1038/ejhg.2010.2
PMCID: PMC2987367  PMID: 20125193
endophenotypes; genome-wide association; cognition; psychiatric conditions; common variants
7.  SVA: software for annotating and visualizing sequenced human genomes 
Bioinformatics  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 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.
Contact: d.ge@duke.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr317
PMCID: PMC3129530  PMID: 21624899
8.  COMT Val108/158 Met Genotype Affects Neural but not Cognitive Processing in Healthy Individuals 
Cerebral Cortex (New York, NY)  2009;20(3):672-683.
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 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.
doi:10.1093/cercor/bhp132
PMCID: PMC2820704  PMID: 19641018
COMT; fMRI; genetic neuroimaging; relational memory
9.  A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB 
Human Molecular Genetics  2009;18(23):4650-4661.
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 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 Cambridge Neuropsychological Test Automated 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 ∼750 subjects, and for spatial and verbal recognition memory, 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. 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.
doi:10.1093/hmg/ddp413
PMCID: PMC2773267  PMID: 19734545
10.  The Characterization of Twenty Sequenced Human Genomes 
PLoS Genetics  2010;6(9):e1001111.
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.
Author Summary
We report here the nearly complete genomic sequence of 20 different individuals, determined using “next-generation” sequencing technologies. We use these data to characterize the type of genetic variation carried by humans in a sample of this size, which is to our knowledge the largest set of unrelated genomic sequences that have been reported. We summarize different categories of variation in each genome, and in total across all 20 of the genomes, finding a surprising number of variants predicted to reduce or remove the proteins encoded by many different genes. This work provides important fundamental information about the scope of human genetic variation, and suggests ways to further explore the relationship between these genetic variants and human disease.
doi:10.1371/journal.pgen.1001111
PMCID: PMC2936541  PMID: 20838461
11.  Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer’s Disease 
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 association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE ε4 risk allele, identified a novel variant that influences disease risk within the APOE ε4 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 line with previous reports, 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.
doi:10.3233/JAD-2010-1212
PMCID: PMC2883723  PMID: 20061627
Alzheimer’s disease; copy number variation; dementia; genome-wide association study
12.  Whole genome association studies in complex diseases: where do we stand? 
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 lateonset 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.
PMCID: PMC3181943  PMID: 20373665
genome-wide association study; rare variant; neuropsychiatric; schizophrenia; sequencing; rare variant; neuropsychiatric; schizophrenia ; sequencing
13.  Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis 
The 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.
doi:10.1038/ejhg.2008.264
PMCID: PMC2986499  PMID: 19156168
schizophrenia; neurocognition; RIMS1; quetiapine; GRM8; discontinuation
15.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci 
PLoS Genetics  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 of α1-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 α-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 1.48×10−10, (rs8034191) and 5.74×10−10 (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.
Author Summary
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.
doi:10.1371/journal.pgen.1000421
PMCID: PMC2650282  PMID: 19300482
16.  A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia 
PLoS Genetics  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 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.
Author Summary
Schizophrenia is a highly heritable disease. While the drugs commonly used to treat schizophrenia offer important relief from some symptoms, other symptoms are not well treated, and the drugs cause serious adverse effects in many individuals. This has fueled intense interest over the years in identifying genetic contributors to schizophrenia. In this paper, we first show that common genetic variants, the focus of most research until recently, do not seem to have a major impact on schizophrenia predisposition. We then provide further evidence that very rare, large DNA deletions and duplications contribute to or explain a minority of schizophrenia cases. Although the small number of events identified here do not restrict focus to a finite set of molecular pathways, we do show one event that deletes a gene known to interact with DISC1, a gene known to cause psychiatric problems in one family. Such convergent findings have potential implications for the development of new therapies and patient subclassifications. We conclude that schizophrenia genetics research must turn sharply toward the identification of rare genetic contributors and that the most important tool in this effort will be complete whole-genome sequencing of patients whose clinical characteristics have been very thoroughly assessed.
doi:10.1371/journal.pgen.1000373
PMCID: PMC2631150  PMID: 19197363
17.  A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans 
Genome Biology  2009;10(1):R7.
A principal components analysis of genomic information showed that individuals with full Jewish ancestry formed a clearly distinct cluster from those individuals with no Jewish ancestry.
Background
It was recently shown that the genetic distinction between self-identified Ashkenazi Jewish and non-Jewish individuals is a prominent component of genome-wide patterns of genetic variation in European Americans. No study however has yet assessed how accurately self-identified (Ashkenazi) Jewish ancestry can be inferred from genomic information, nor whether the degree of Jewish ancestry can be inferred among individuals with fewer than four Jewish grandparents.
Results
Using a principal components analysis, we found that the individuals with full Jewish ancestry formed a clearly distinct cluster from those individuals with no Jewish ancestry. Using the position on the first principal component axis, every single individual with self-reported full Jewish ancestry had a higher score than any individual with no Jewish ancestry.
Conclusions
Here we show that within Americans of European ancestry there is a perfect genetic corollary of Jewish ancestry which, in principle, would permit near perfect genetic inference of Ashkenazi Jewish ancestry. In fact, even subjects with a single Jewish grandparent can be statistically distinguished from those without Jewish ancestry. We also found that subjects with Jewish ancestry were slightly more heterozygous than the subjects with no Jewish ancestry, suggesting that the genetic distinction between Jews and non-Jews may be more attributable to a Near-Eastern origin for Jewish populations than to population bottlenecks.
doi:10.1186/gb-2009-10-1-r7
PMCID: PMC2687795  PMID: 19161619
18.  Large recurrent microdeletions associated with schizophrenia 
Stefansson, Hreinn | Rujescu, Dan | Cichon, Sven | Pietiläinen, Olli P. H. | Ingason, Andres | Steinberg, Stacy | Fossdal, Ragnheidur | Sigurdsson, Engilbert | Sigmundsson, Thordur | Buizer-Voskamp, Jacobine E. | Hansen, Thomas | Jakobsen, Klaus D. | Muglia, Pierandrea | Francks, Clyde | Matthews, Paul M. | Gylfason, Arnaldur | Halldorsson, Bjarni V. | Gudbjartsson, Daniel | Thorgeirsson, Thorgeir E. | Sigurdsson, Asgeir | Jonasdottir, Adalbjorg | Jonasdottir, Aslaug | Bjornsson, Asgeir | Mattiasdottir, Sigurborg | Blondal, Thorarinn | Haraldsson, Magnus | Magnusdottir, Brynja B. | Giegling, Ina | Möller, Hans-Jürgen | Hartmann, Annette | Shianna, Kevin V. | Ge, Dongliang | Need, Anna C. | Crombie, Caroline | Fraser, Gillian | Walker, Nicholas | Lonnqvist, Jouko | Suvisaari, Jaana | Tuulio-Henriksson, Annamarie | Paunio, Tiina | Toulopoulou, Timi | Bramon, Elvira | Di Forti, Marta | Murray, Robin | Ruggeri, Mirella | Vassos, Evangelos | Tosato, Sarah | Walshe, Muriel | Li, Tao | Vasilescu, Catalina | Mühleisen, Thomas W. | Wang, August G. | Ullum, Henrik | Djurovic, Srdjan | Melle, Ingrid | Olesen, Jes | Kiemeney, Lambertus A. | Franke, Barbara | Kahn, René S. | Linszen, Don H. | van Os, Jim | Wiersma, Durk | Bruggeman, Richard | Cahn, Wiepke | de Haan, Lieuwe | Krabbendam, Lydia | Myin-Germeys, Inez | Sabatti, Chiara | Freimer, Nelson B. | Gulcher, Jeffrey R. | Thorsteinsdottir, Unnur | Kong, Augustine | Andreassen, Ole A. | Ophoff, Roel A. | Georgi, Alexander | Rietschel, Marcella | Werge, Thomas | Petursson, Hannes | Goldstein, David B. | Nöthen, Markus M. | Peltonen, Leena | Collier, David A. | Clair, David St | Stefansson, Kari
Nature  2008;455(7210):232-236.
Reduced fecundity, associated with severe mental disorders1, 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 autism2 schizophrenia3 and mental retardation4. 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 retardation4,5 and autism2. 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.
doi:10.1038/nature07229
PMCID: PMC2687075  PMID: 18668039
19.  Control of Axonal Growth and Regeneration of Sensory Neurons by the p110δ PI 3-Kinase 
PLoS ONE  2007;2(9):e869.
The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (PI3K) in the nervous system are unknown. Whereas most PI3Ks have a broad tissue distribution, the tyrosine kinase-linked p110δ isoform has previously been shown to be enriched in leukocytes. Here we report that p110δ is also highly expressed in the nervous system. Inactivation of p110δ in mice did not affect gross neuronal development but led to an increased vulnerability of dorsal root ganglia neurons to exhibit growth cone collapse and decreases in axonal extension. Loss of p110δ activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110δ inactivation resulted in reduced neuronal signaling through the Akt protein kinase, and increased activity of the small GTPase RhoA. Pharmacological inhibition of ROCK, a downstream effector of RhoA, restored axonal extension defects in neurons with inactive p110δ, suggesting a key role of RhoA in p110δ signaling in neurons. Our data identify p110δ as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.
doi:10.1371/journal.pone.0000869
PMCID: PMC1959241  PMID: 17846664

Results 1-19 (19)