2014 Sustainability Report · 2018-03-122014 Sustainability Report
122014 V71I12- A Breakthrough in Schizophrenia Genetics
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Copia autorizada por CDR Copyright 2014 American Medical Association. All rights reserved. A Breakthrough in Schizophrenia Genetics The effort to understand the nature of the genetic risk for schizophrenia began more than 100 years ago. Since then, many studies have confirmed schizophrenia is strongly familial, largely as a result of genetic factors. As molecular genetic methods became available in the 1980s, serious interest turned to trying to identify the nature of this risk. It has proven a long and difficult road. A recent article from the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) represents an important landmark on this journey. 1 The study started with a primary sample of 49 nonoverlap- ping case-control samples (34 241 cases and 45 604 controls) and 3 family-based samples of European an- cestry (1235 parent affected–offspring trios). For mark- ers showing suggestive evidence for association, sum- mary data were added based on genotypes from 1513 cases and 66 236 controls of European ancestry. To- gether, these samples identified 128 independent asso- ciations from 108 loci that met criteria for genome- wide significance. Eighty-three of these loci had not been previously reported. Multiple efforts were taken to en- sure that these results were not artifactual and that most of the reported associations were true positives. The PGC article teaches us at least 9 important les- sons. First, genetic risk for schizophrenia is widely dis- bursed across the genome and includes many loci of small effect. This emergent genetic architecture re- sembles that being discovered for many other complex biomedical disorders and traits. Second, although the functional variants responsible have yet to be charac- terized, the genome-wide association (GWA) approach to schizophrenia has succeeded in its main task of iden- tifying associations with common risk alleles, from 3 loci in 2009, 2 17 loci in 2012, 3 and now 108 risk loci in 2014. The job is, however, far from complete. All indications are that further gene discoveries will emerge as sample size increases, although we do not yet know when such gains will start to asymptote. Third, the rapid escala- tion in the rate of schizophrenia locus discovery was only possible by a change in research culture in which many groups were willing to share their primary genotypic and phenotypic data. Fourth, these important results raise new critical questions. Long lists of weak risk variants are on their own of limited scientific importance. The most impor- tant aspect of such discoveries is the possibility that they will permit identification of disease pathways. 4 An “eye- ball” examination already suggests possible leads in- cluding multiple genes involved in glutamatergic trans- mission, calcium channels, and immune function. Such “network analyses” are emerging as an important area of research development and bring a host of challeng- ing biological and statistical questions. Of course, the big- ger the list of variants, the more chances there will be to detect critical patterns and pathways. So this effort would be aided by increasing the available size of GWA schizophrenia samples. A potential critical payoff of such efforts would be identification of novel targets for drug development, a prospect that is encouraged by the iden- tification in the current study of multiple associations with genes in networks that are already high-priority therapeutic targets. As we identify credible risk genes, we also present the neuroscience community with the major challenge of understanding the processes by which alterations in the structure or expression of these genes produce neurobiological changes, which in turn increase the vulnerability to develop positive and nega- tive schizophrenic symptoms. Fifth, we can now ask increasingly informative ques- tions about the genomic distribution of risk variants to address etiological hypotheses. The PGC article pre- sents several such preliminary analyses. An examina- tion of epigenetic markers characteristic of active en- hancers showed that schizophrenia associations are significantly enriched at enhancers active in the brain, particularly cortical and striatal neurons. Moreover, in- dependent of those active in the brain, schizophrenia as- sociations were significantly enriched at enhancers ac- tive in immune tissues, especially B-lymphocyte lineages. Sixth, GWA interrogates only part of the “effect size/ allele frequency” space of genetic risks for complex dis- orders—in particular common variants. Research is ac- tive in 2 other “spaces”: rare variants detectable by exome (and increasingly whole-genome) sequencing and large genomic changes resulting from copy number vari- ants. The relative importance of these 3 sources of ge- netic risk is still unclear, although mounting evidence points to the importance of common small effect vari- ants. The PGC article also notes a trend for common and rare risk variants to occur in the same genes, a develop- ment that confirms the view that efforts to identify these classes of risk variants can be viewed as different routes to the same destination. Seventh, psychiatric genetic research can usefully inform psychiatric diagnosis and vice versa. Already, using aggregate genetic signals derived from GWA, substantial sharing of genetic risk has been shown across some psychiatric disorders. 5 This can now be done profitably at the level of individual variants or genes. For example, this report notes a statistically significant overlap between the GWA variants identi- fied for schizophrenia and de novo nonsynonymous mutations for intellectual disability and autism spec- trum disorders, an overlap already shown for rare genetic variation. Eighth, most discussions about gene discovery in psychiatry appropriately focus on biology, but it is now worthwhile to explore the public health implications of these findings. The PGC article examined the ability of risk profile scores to identify risk of illness in 3 geno- VIEWPOINT Kenneth S. Kendler, MD Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond; Department of Psychiatry, Virginia Commonwealth University, Richmond; and Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond. Michael C. O'Donovan, MD MRC Centre for Psychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales. Corresponding Author: Kenneth S. Kendler, MD, Virginia Commonwealth University, PO Box 980126, MCV, Richmond, VA 23220 ([email protected]). Opinion jamapsychiatry.com JAMA Psychiatry December 2014 Volume 71, Number 12 1319 Copyright 2014 American Medical Association. All rights reserved. Downloaded From: http://archpsyc.jamanetwork.com/ by a Pfizer Inc User on 01/14/2015 15/01/2015
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Copyright 2014 American Medical Association. All rights reserved.
A Breakthrough in Schizophrenia Genetics
Theeffort tounderstand thenatureof thegenetic riskfor schizophreniabeganmore than 100years ago. Sincethen, many studies have confirmed schizophrenia isstrongly familial, largely as a result of genetic factors. Asmolecular genetic methods became available in the1980s, serious interest turned to trying to identify thenatureof this risk. It hasprovena longanddifficult road.
A recent article from the Schizophrenia WorkingGroup of the Psychiatric Genomics Consortium (PGC)represents an important landmarkon this journey.1 Thestudy startedwith a primary sample of 49 nonoverlap-ping case-control samples (34 241 cases and 45 604controls) and 3 family-based samples of European an-cestry (1235 parent affectedoffspring trios). Formark-ers showing suggestive evidence for association, sum-mary data were added based on genotypes from 1513cases and 66 236 controls of European ancestry. To-gether, these samples identified 128 independent asso-ciations from 108 loci that met criteria for genome-widesignificance.Eighty-threeof these locihadnotbeenpreviously reported. Multiple efforts were taken to en-sure that these resultswerenotartifactual andthatmostof the reported associations were true positives.
The PGC article teaches us at least 9 important les-sons. First, genetic risk for schizophrenia is widely dis-bursed across the genome and includes many loci ofsmall effect. This emergent genetic architecture re-sembles that beingdiscovered formanyother complexbiomedical disorders and traits. Second, although thefunctional variants responsible have yet to be charac-terized, the genome-wide association (GWA) approachto schizophrenia has succeeded in itsmain taskof iden-tifyingassociationswith commonrisk alleles, from3 lociin 2009,2 17 loci in 2012,3 and now 108 risk loci in 2014.The job is, however, far from complete. All indicationsare that further gene discoverieswill emerge as samplesize increases, althoughwedonot yet knowwhen suchgains will start to asymptote. Third, the rapid escala-tion in the rateof schizophrenia locusdiscoverywasonlypossible by a change in research culture in whichmanygroupswerewilling toshare theirprimarygenotypicandphenotypic data.
Fourth, these important results raise new criticalquestions. Long lists of weak risk variants are on theirown of limited scientific importance. The most impor-tantaspectof suchdiscoveries is thepossibility that theywill permit identificationofdiseasepathways.4An eye-ball examination already suggests possible leads in-cludingmultiple genes involved in glutamatergic trans-mission, calcium channels, and immune function. Suchnetwork analyses are emerging as an important areaof research development and bring a host of challeng-ingbiologicalandstatisticalquestions.Ofcourse, thebig-ger the list of variants, the more chances there will beto detect critical patterns and pathways. So this effort
would be aided by increasing the available size of GWAschizophreniasamples.Apotential criticalpayoffof sucheffortswould be identification of novel targets for drugdevelopment,aprospect that isencouragedbythe iden-tification in the current study of multiple associationswith genes in networks that are already high-prioritytherapeutic targets. As we identify credible risk genes,we also present the neuroscience community with themajor challenge of understanding the processes bywhichalterations in the structureor expressionof thesegenes produce neurobiological changes, which in turnincrease thevulnerability todeveloppositive andnega-tive schizophrenic symptoms.
Fifth,wecannowask increasingly informativeques-tions about the genomic distribution of risk variants toaddress etiological hypotheses. The PGC article pre-sents several such preliminary analyses. An examina-tion of epigenetic markers characteristic of active en-hancers showed that schizophrenia associations aresignificantly enriched at enhancers active in the brain,particularly cortical and striatal neurons. Moreover, in-dependentof thoseactive in thebrain, schizophreniaas-sociations were significantly enriched at enhancers ac-tive in immunetissues,especiallyB-lymphocyte lineages.
Sixth,GWAinterrogatesonlypartof theeffect size/allele frequency spaceof genetic risks for complexdis-ordersin particular common variants. Research is ac-tive in 2 other spaces: rare variants detectable byexome(andincreasinglywhole-genome)sequencingandlargegenomicchanges resulting fromcopynumbervari-ants. The relative importance of these 3 sources of ge-netic risk is still unclear, although mounting evidencepoints to the importance of common small effect vari-ants. ThePGCarticle alsonotes a trend for commonandrare risk variants to occur in the samegenes, a develop-ment thatconfirmstheviewthatefforts to identify theseclassesof risk variants canbeviewedasdifferent routesto the same destination.
Seventh, psychiatric genetic research can usefullyinform psychiatric diagnosis and vice versa. Already,using aggregate genetic signals derived from GWA,substantial sharing of genetic risk has been shownacross some psychiatric disorders.5 This can now bedone profitably at the level of individual variants orgenes. For example, this report notes a statisticallysignificant overlap between the GWA variants identi-fied for schizophrenia and de novo nonsynonymousmutations for intellectual disability and autism spec-trum disorders, an overlap already shown for raregenetic variation.
Eighth, most discussions about gene discovery inpsychiatry appropriately focus on biology, but it is nowworthwhile to explore the public health implications ofthese findings. The PGC article examined the ability ofrisk profile scores to identify risk of illness in 3 geno-
VIEWPOINT
Kenneth S. Kendler,MDVirginia Institute forPsychiatric andBehavioral Genetics,VirginiaCommonwealthUniversity, Richmond;Department ofPsychiatry, VirginiaCommonwealthUniversity, Richmond;and Department ofHuman andMolecularGenetics, VirginiaCommonwealthUniversity, Richmond.
Michael C.O'Donovan,MDMRC Centre forPsychiatric Geneticsand Genomics, CardiffUniversity, Cardiff,Wales.
CorrespondingAuthor: Kenneth S.Kendler, MD, VirginiaCommonwealthUniversity, PO Box980126, MCV,Richmond, VA 23220([email protected]).
Opinion
jamapsychiatry.com JAMAPsychiatry December 2014 Volume 71, Number 12 1319
Copyright 2014 American Medical Association. All rights reserved.
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15/01/2015
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Copyright 2014 American Medical Association. All rights reserved.
typed population samples. When the risk scores were divided intodeciles, the odds ratio for schizophrenia in the highest vs lowestdecile ranged from 8 to 20. We have a long way to go before clini-callyorepidemiologicallyuseful applicationscanbemade fromsuchdata. However, these results suggest that, in principle, combininglarge numbers of weak risk alleles can result in substantial aggre-gate predictive power for risk of illness.
Finally, theseandother recent results should retire aneffort go-ing back to the roots of psychiatric genetics to find the mendeliannatureofschizophrenia.Throughoutmuchof itshistory,modernpsy-chiatry has sought to ground its categorical diagnostic approachesin basic biological findings. One such effort was to locate the genefor schizophrenia. It is now widely agreed that no such gene ex-ists. Rather, the genetic vulnerability to this tragic disease is widelydistributed across the genome in a way that resembles the multi-factorial threshold models so popular for years in statistical genet-
ics. This has 2 noteworthy implications. First, the old divisions be-tween psychiatric genetic epidemiologists (who studied families,twins, and adoptions) and molecular geneticistswhere the for-mer did just statistics and the latter studied real genesshouldcrumble. Indeed, the twin researchers, usingmultifactorial thresh-oldmodels, probably had amore accurate geneticmodel of psychi-atric illness than molecular researchers doing linkage and candi-date gene association analysis, who typically assumed single-locusmodels of relatively large effect. Statistical andmolecular tools willneedtobefully integrated in theyearsahead.Second,andmorepro-foundly, while there is surely a discrete phenomenological state ofpsychosis that clinicians can agree about reliably, there is no suchdichotomy at the level of genetic risk. All of us carry schizophreniarisk variants, and the vast majority of us carry quite a lot of them.With respect to genetic risk, there is no themand us, only subtleshades of gray.
ARTICLE INFORMATION
Published Online:October 1, 2014.doi:10.1001/jamapsychiatry.2014.1776.
Conflict of Interest Disclosures:None reported.
Additional Contributions:We acknowledgemorethan 100 000 research participants and 300researchers whose work forms the foundation ofthis commentary.
REFERENCES
1. SchizophreniaWorking Group of the PsychiatricGenomics Consortium. Biological insights from 108schizophrenia-associated genetic loci. Nature.2014;511(7510):421-427.
2. Stefansson H, Ophoff RA, Steinberg S, et al;Genetic Risk and Outcome in Psychosis (GROUP).Common variants conferring risk of schizophrenia.Nature. 2009;460(7256):744-747.
3. Sullivan PF, Daly MJ, ODonovanM. Geneticarchitectures of psychiatric disorders: the emergingpicture and its implications. Nat Rev Genet. 2012;13(8):537-551.
4. Kendler KS. What psychiatric genetics hastaught us about the nature of psychiatric illness andwhat is left to learn.Mol Psychiatry. 2013;18(10):1058-1066.
5. Lee SH, Ripke S, Neale BM, et al; Cross-DisorderGroup of the Psychiatric Genomics Consortium;
International Inflammatory Bowel Disease GeneticsConsortium (IIBDGC). Genetic relationship betweenfive psychiatric disorders estimated fromgenome-wide SNPs.Nat Genet. 2013;45(9):984-994.
Opinion Viewpoint
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