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Identificación de genes con efectos compartidos en trastornos psiquiátricos

Identificación de genes con efectos compartidos en trastornos psiquiátricos

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www.thelancet.com
 
Published online February 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62129-1
1
Identification of risk loci with shared effects on five majorpsychiatric disorders: a genome-wide analysis
Cross-Disorder Group of the Psychiatric Genomics Consortium*
Summary
Background
Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do notin all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effectsshared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attentiondeficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.
Methods
We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 casesand 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomiallogistic regression procedure with model selection to identify the best-fitting model of relations between genotypeand phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlapfor the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.
Findings
SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10
⁸) in the primary analysis:regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits,
CACNA1C 
and
CACNB2 
. Model selection analysis supported effects of these loci for several disorders. Loci previouslyassociated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showedcross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calciumchannel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enrichedfor brain eQTL markers.
Interpretation
Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhoodonset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects onpsychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes inpsychiatry, and towards a nosology informed by disease cause.
Funding
National Institute of Mental Health.
Introduction
Psychiatric nosology arose in central Europe towards theend of the 19th century, in particular with Kraepelin’sfoundational distinction between dementia praecox(schizophrenia) and manic depressive insanity.
1
Thedistinction between bipolar illness and unipolar (major)depression was first proposed in the late 1950s andbecame increasingly widely accepted. The major syn-dromes—especially schizophrenia, bipolar disorder, andmajor depression—were differentiated on the basis of their symptom patterns and course of illness. At thesame time, clinical features such as psychosis, mooddysregulation, and cognitive impairments were knownto transcend diagnostic categories. Doubt remainsabout the boundaries between the syndromes and thedegree to which they signify entirely distinct entities,disorders that have overlapping foundations, or differentvariants of one underlying disease. Such debates haveintensified with syndromes described subsequently,including autism spectrum disorders and attentiondeficit-hyperactivity disorder.The pathogenic mechanisms of psychiatric disordersare largely unknown, so diagnostic boundaries arediffi cult to define. Genetic risk factors are important inthe causation of all major psychiatric disorders,
2
andgenetic strategies are widely used to assess potentialoverlaps. The imminent revision of psychiatric classifi-cations in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classifi-cation of Diseases (ICD) has reinvigorated debate aboutthe validity of diagnostic boundaries. With increasingavailability of large genome-wide genotype data forseveral psychiatric disorders, shared cause can now beexamined at a molecular level.We formed the Psychiatric Genomics Consortium(PGC) in 2007, to undertake meta-analyses of genome-wide association studies (GWAS) for psychiatric dis-orders and, so far, the consortium has incorporatedGWAS data from more than 19 countries for schizo-phrenia, bipolar disorder, major depressive disorder,attention deficit-hyperactivity disorder, and autismspectrum disorders. Previous research has suggested
Published
Online
February 28, 2013http://dx.doi.org/10.1016/S0140-6736(12)62129-1See
Online/Comment
http://dx.doi.org/10.1016/S0140-6736(13)60223-8*Members listed at end of paperCorrespondence to:Dr Jordan W Smoller, SimchesResearch Building,Massachusetts General Hospital,Boston, MA 02114, USA
 jsmoller@hms.harvard.edu
 
Articles
2
www.thelancet.com
 
Published online February 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62129-1
varying degrees of overlap in familial and genetic liabilityfor pairs of these disorders. For example, some findings
3,4 
 from family and twin studies support diagnostic boun-daries between schizophrenia and bipolar disorder andbipolar disorder and major depressive disorder, but alsosuggest correlations in familial and genetic liabilities.
3,5
 Several molecular variants confer risk of both schizo-phrenia and bipolar disorder.
6–8
Autism was once knownas childhood schizophrenia and the two disorders werenot clearly differentiated until the 1970s. Findings fromthe past few years have emphasised phenotypic andgenetic overlap between autism spectrum disorders andschizophrenia,
9,10
including identification of copy numbervariants conferring risk of both.
11
Findings from family,twin, and molecular studies
12–15
suggest some geneticoverlap between autism spectrum disorder and attentiondeficit-hyperactivity disorder.In this first report from the PGC Cross-Disorder Group,we analyse data on genome-wide single-nucleotide poly-morphism (SNP) for the five PGC disorders to answer twoquestions. First, what information emerges when all fivedisorders are examined in one GWAS? When risk iscorrelated across disorders, pooled analyses will be betterpowered than individual-disorder analyses to detect riskloci. Second, what are the cross-disorder effects of variantsalready identified as being associated with a specificpsychiatric disorder in previous PGC analyses? We aimedto examine the genetic relation between the five psychiatricdisorders with the expectation that findings will ultimatelyinform psychiatric nosology, identify potential neuro-biological mechanisms predisposing to specific clinicalpresentations, and generate new models for preventionand treatment.
Methods
Samples and genotypes
The sample for these analyses consisted of cases,controls, and family-based samples assembled forprevious genome-wide PGC mega-analyses of individual-level data.
6,7,16,17
Cases and controls were not related. Forthe family-based samples, we matched alleles transmittedto affected offspring (trio cases) with untransmittedalleles (pseudocontrols). We estimated the identity-by-descent relation for all pairs of individuals to identify anyduplicate individuals in the component datasets. Whenduplicates were detected, one member of each set wasretained. We then randomly allocated these individuals,with a random number generator, to a disorder case-control dataset. Sample sizes differ from previous reportsbecause of this allocation of overlapping individuals. Allpatients were of European ancestory and met criteriafrom the DSM third edition revised or fourth edition forthe primary disorder of interest.To ensure comparability between samples, raw geno-type and phenotype data for each study were uploadedto a central server and processed through the samequality control, imputation, and analysis process(appendix).
6,7
We analysed imputed SNP dosages from1 250 922 autosomal SNPs.
Statistical analysis
In the primary analysis, we combined effects of eachdisease analysis by a meta-analytic approach that applieda weighted
-score,
18
in which weights equalled theinverse of the regression coeffi cient’s standard error.This strategy assumed a fixed-effects model, with weightsindicating the sample size of the disease-specific studies.In a second analytical approach, we did a five-degree-of-freedom test by summing the χ² values for eachindividual disease meta-analysis. Unlike our primaryanalysis, this model did not assume that all diseases hadthe same direction of effect and could detect allelic effectsthat increase risk for some diseases and decrease risk forothers. The appendix describes statistical methods andresults, including the handling of trios and populationstratification. We also examined loci that previouslyachieved genome-wide significance in PGC meta-analyses of schizophrenia and bipolar disorder.
6,7
To characterise the specificity of the allelic effects forour main findings, we examined the association evidencein three ways: we generated forest plots of the disorderbeta coeffi cients with 95% CIs; we calculated a hetero-geneity p value for the disorder-specific effects con-tributing to the overall statistics for meta-analyticassociation; and we undertook a multinomial logisticregression procedure with model selection
19
for eachmain SNP for all five disorders to assess the pattern of phenotypic effects (appendix pp 8–11). To compare the fitof various models of genotype–phenotype associations,we applied established goodness-of-fit metrics (theBayesian information criteria and the Akaike informationcriteria). We report the best-fitting model by Bayesiancriteria and show results of both metrics for a range of models (appendix pp 38–45, 51–61).To examine shared polygenic risk at an aggregate levelbetween pairs of diagnoses, we used risk-score profiling aspreviously described.
8
For each pair, we selected onedisorder as a discovery dataset and the other as a targetdataset and calculated the proportion of variance in thetarget set explained by risk scores from the discovery setwith a range of statistical cutoffs for SNP inclusion in thescore (appendix p 13). To assess the role of specificbiological systems in the pathogenesis of the five disorders,we did pathway and eQTL analyses. Pathway analysis wasby interval-based enrichment analysis (INRICH) for thefull dataset consisting of linkage disequilibrium segmentscontaining signals with association p<10
³ in the primarymeta-analysis. INRICH accounts for potential genomicconfounding factors, such as variable gene and pathwaysizes, SNP density, linkage disequilibrium, and physicalclustering of biologically related genes (appendix pp 14–16).We did eQTL enrichment analysis
20
to assess whetherSNPs associated with five psychiatric disorders wereenriched for regulatory SNPs in post-mortem brain tissue
See
Online
for appendixFor
INRICH
see http://atgu.mgh.harvard.edu/inrich
 
Articles
www.thelancet.com
 
Published online February 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62129-1
3
samples compared with those with no association.
21,22
Toassess the specificity of this finding, we also examinedeQTL datasets from three non-brain-tissue types: liver,
23
 skin,
24 
and lymphoblastoid cell lines
25
(appendix pp 17–21).
Role of the funding source
The sponsor of the study had no role in study design,data collection, data analysis, data interpretation, orwriting of the report. The corresponding author had fullaccess to all the data and had final responsibility for thedecision to submit for publication.
Results
The final dataset consisted of 33 332 cases and 27 888 con-trols (including pseudocontrols formed from non-transmitted alleles) distributed among the five disordergroups: autism spectrum disorders (4788 trio cases,4788 trio pseudocontrols, 161 cases, 526 controls),attention deficit-hyperactivity disorder (1947 trio cases,1947 trio pseudocontrols, 840 cases, 688 controls),bipolar disorder (6990 cases, 4820 controls), majordepressive disorder (9227 cases, 7383 controls), andschizophrenia (9379 cases, 7736 controls). The results of the primary fixed-effects meta-analysis for all fivedisorders, incorporating seven multidimensional scalingcomponents as covariates, yielded a genomic controlvalue of λ=1·167. The λ 
1000
(λ rescaled to a sample of 1000 cases and 1000 controls) was 1·005 (appendix p 22).In view of evidence for substantial polygenic con-tributions to common psychiatric disorders, thisestimate probably shows the aggregate small effect of alarge number of risk variants, although a moderate
Figure 1:
Manhattan plot of primary fixed-effects meta-analysis
Horizontal line shows threshold for genome-wide significance (p<5×10⁸).
123456789101112131415161718192021221234567891011121314
  –    l   o   g
    1    0
     (   p    v   a    l   u   e    )
Chromosome
MIR137 (+1)ITIH3 (+35)HINT1 (+7)MHC (369)ZFPM2CACNB2CACNA1CCPNE7 (+12)TCF4NEURL (+25)SYNE1FPR2 (+11)
ChromosomeBase-pairposition*Nearest geneAllelesFrequencyImputation qualityscore (INFO)p valueOR (95% CI)Heterogeneityp valueBest-fit model(BIC)§
rs2535629352808259
ITIH3
(+ many)G/A0·6510·9422·54×10¹²1·10 (1·071·12)0·27Five disorderrs1119145410104649994
 AS3MT 
(
+
many)A/G0·9101·011·39×101·13 (1·08 1·18)0·32Five disorderrs1024582122272507
CACNA1C 
A/G0·3370·981·87×101·07 (1·05-1·10)0·0057BPD, schizophreniars27995731018641934
CACNB2
T/C0·7150·8254·29×101·08 (1·05-1·12)0·57Five disorder
Most strongly associated single-nucleotide polymorphisms (SNP) in associated region after clumping—ie, grouping SNPs within 250 kb of the index SNP that have
²>0·2 with the index SNP as implemented inPLINK. OR=odds ratio. BIC=Bayesian information criteria. BPD=bipolar disorder. *Detected with University of California Santa Cruz Genome Browser (version hg18). †Risk allele frequency in controls.
EstimatedOR from multinomial logistic regression used in the modelling analysis.
§
Best-fit multinomial logistic model by BIC criteria; appendix pp 38–45 provide a comparison of BIC and Akaike information criteria acrossmodels. ¶Best-fit model supports an effect on all five disorders.
Table 1:
Five disorder meta-analysis results for regions with p<5×10⁸

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