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Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci.

Andreassen OA, Harbo HF, Wang Y, Thompson WK, Schork AJ, Mattingsdal M, Zuber V, Bettella F, Ripke S, Kelsoe JR, Kendler KS, O'Donovan MC, Sklar P, Psychiatric Genomics Consortium (PGC) Bipolar Disorder and Schizophrenia Work GroupsInternational Multiple Sclerosis Genetics Consortium (IMSGC)McEvoy LK, Desikan RS, Lie BA, Djurovic S, Dale AM - Mol. Psychiatry (2014)

Bottom Line: We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS.In contrast, we found no genetic overlap between BD and MS.Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

View Article: PubMed Central - PubMed

Affiliation: 1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.

ABSTRACT
Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21,856) and multiple sclerosis (MS) (n=43,879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16,731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

No MeSH data available.


Related in: MedlinePlus

Genetic pleiotropy enrichment of schizophrenia (SCZ) conditional on MS. (a) Conditional Q-Q plot of nominal versus empirical −log10P-values (corrected for inflation) in SCZ below the standard GWAS threshold of P<5 × 10−8 as a function of significance of association with multiple sclerosis (MS) at the level of −log10(P)⩾0, −log10(P)⩾1, −log10(P)⩾2, −log10(P)⩾3 corresponding to P⩽1, P⩽0.1, P⩽0.01, P⩽0.001, respectively. Dotted lines indicate the  hypothesis. (b) Conditional true discovery rate (TDR) plots illustrating the increase in TDR associated with increased pleiotropic enrichment in SCZ conditioned on MS (SCZ/MS). (c) Cumulative replication plot showing the average rate of replication (P<0.05) within SCZ substudies for a given P-value threshold shows that pleiotropic enriched SNP categories replicate at a higher rate in independent SCZ samples, for SCZ conditioned on MS (SCZ/MS). The vertical intercept is the overall replication rate per category. (d) Z-score-z-score plot demonstrates that the empirical replication z-scores closely match the expected a posteriori effect sizes of SCZ and are strongly dependent upon pleiotropy with MS. Analysis is based on split half method of the 17 PGC SCZ substudies.
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fig1: Genetic pleiotropy enrichment of schizophrenia (SCZ) conditional on MS. (a) Conditional Q-Q plot of nominal versus empirical −log10P-values (corrected for inflation) in SCZ below the standard GWAS threshold of P<5 × 10−8 as a function of significance of association with multiple sclerosis (MS) at the level of −log10(P)⩾0, −log10(P)⩾1, −log10(P)⩾2, −log10(P)⩾3 corresponding to P⩽1, P⩽0.1, P⩽0.01, P⩽0.001, respectively. Dotted lines indicate the hypothesis. (b) Conditional true discovery rate (TDR) plots illustrating the increase in TDR associated with increased pleiotropic enrichment in SCZ conditioned on MS (SCZ/MS). (c) Cumulative replication plot showing the average rate of replication (P<0.05) within SCZ substudies for a given P-value threshold shows that pleiotropic enriched SNP categories replicate at a higher rate in independent SCZ samples, for SCZ conditioned on MS (SCZ/MS). The vertical intercept is the overall replication rate per category. (d) Z-score-z-score plot demonstrates that the empirical replication z-scores closely match the expected a posteriori effect sizes of SCZ and are strongly dependent upon pleiotropy with MS. Analysis is based on split half method of the 17 PGC SCZ substudies.

Mentions: To visually assess pleiotropic enrichment, we used Q-Q plots conditioned on ‘pleiotropic' effects14,24 (Figures 1a and 2a for BD). For a given associated phenotype, pleiotropic ‘enrichment' exists if the degree of deflection from the expected line is dependent on associations with the second phenotype (for further details see Supplementary Information). We constructed conditional Q-Q plots of empirical quantiles of nominal –log10(P) values for all SNPs and for subsets of SNPs determined by the significance of their association with MS. Specifically, we computed the empirical cumulative distribution function (ecdf) of nominal P-values for a given phenotype for all SNPs and for SNPs with significance levels below the indicated cutoffs for the other phenotype (–log10(P)⩾0, –log10(P)⩾1, –log10(P) ⩾2, –log10(P) ⩾3 corresponding to P⩽1, P⩽0.1, P⩽0.01, P⩽0.001, respectively). Nominal P-values (–log10(P)) are plotted on the y-axis, and empirical quantiles (–log10(q), where q=1−ecdf(P)) are plotted on the x-axis. To assess polygenic effects below the standard GWAS significance threshold, we focused the Q-Q plots on SNPs with nominal –log10(P)<7.3 (corresponding to P>5 × 10−8). The same procedure was used for BD. The ‘enrichment' seen in the conditional Q-Q plots can be directly interpreted in terms of true discovery rate (TDR=1− FDR).29 This is illustrated in Figures 1b and 2b for each range of P-values in the pleiotropic traits (see Supplementary Information for details).


Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci.

Andreassen OA, Harbo HF, Wang Y, Thompson WK, Schork AJ, Mattingsdal M, Zuber V, Bettella F, Ripke S, Kelsoe JR, Kendler KS, O'Donovan MC, Sklar P, Psychiatric Genomics Consortium (PGC) Bipolar Disorder and Schizophrenia Work GroupsInternational Multiple Sclerosis Genetics Consortium (IMSGC)McEvoy LK, Desikan RS, Lie BA, Djurovic S, Dale AM - Mol. Psychiatry (2014)

Genetic pleiotropy enrichment of schizophrenia (SCZ) conditional on MS. (a) Conditional Q-Q plot of nominal versus empirical −log10P-values (corrected for inflation) in SCZ below the standard GWAS threshold of P<5 × 10−8 as a function of significance of association with multiple sclerosis (MS) at the level of −log10(P)⩾0, −log10(P)⩾1, −log10(P)⩾2, −log10(P)⩾3 corresponding to P⩽1, P⩽0.1, P⩽0.01, P⩽0.001, respectively. Dotted lines indicate the  hypothesis. (b) Conditional true discovery rate (TDR) plots illustrating the increase in TDR associated with increased pleiotropic enrichment in SCZ conditioned on MS (SCZ/MS). (c) Cumulative replication plot showing the average rate of replication (P<0.05) within SCZ substudies for a given P-value threshold shows that pleiotropic enriched SNP categories replicate at a higher rate in independent SCZ samples, for SCZ conditioned on MS (SCZ/MS). The vertical intercept is the overall replication rate per category. (d) Z-score-z-score plot demonstrates that the empirical replication z-scores closely match the expected a posteriori effect sizes of SCZ and are strongly dependent upon pleiotropy with MS. Analysis is based on split half method of the 17 PGC SCZ substudies.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4356743&req=5

fig1: Genetic pleiotropy enrichment of schizophrenia (SCZ) conditional on MS. (a) Conditional Q-Q plot of nominal versus empirical −log10P-values (corrected for inflation) in SCZ below the standard GWAS threshold of P<5 × 10−8 as a function of significance of association with multiple sclerosis (MS) at the level of −log10(P)⩾0, −log10(P)⩾1, −log10(P)⩾2, −log10(P)⩾3 corresponding to P⩽1, P⩽0.1, P⩽0.01, P⩽0.001, respectively. Dotted lines indicate the hypothesis. (b) Conditional true discovery rate (TDR) plots illustrating the increase in TDR associated with increased pleiotropic enrichment in SCZ conditioned on MS (SCZ/MS). (c) Cumulative replication plot showing the average rate of replication (P<0.05) within SCZ substudies for a given P-value threshold shows that pleiotropic enriched SNP categories replicate at a higher rate in independent SCZ samples, for SCZ conditioned on MS (SCZ/MS). The vertical intercept is the overall replication rate per category. (d) Z-score-z-score plot demonstrates that the empirical replication z-scores closely match the expected a posteriori effect sizes of SCZ and are strongly dependent upon pleiotropy with MS. Analysis is based on split half method of the 17 PGC SCZ substudies.
Mentions: To visually assess pleiotropic enrichment, we used Q-Q plots conditioned on ‘pleiotropic' effects14,24 (Figures 1a and 2a for BD). For a given associated phenotype, pleiotropic ‘enrichment' exists if the degree of deflection from the expected line is dependent on associations with the second phenotype (for further details see Supplementary Information). We constructed conditional Q-Q plots of empirical quantiles of nominal –log10(P) values for all SNPs and for subsets of SNPs determined by the significance of their association with MS. Specifically, we computed the empirical cumulative distribution function (ecdf) of nominal P-values for a given phenotype for all SNPs and for SNPs with significance levels below the indicated cutoffs for the other phenotype (–log10(P)⩾0, –log10(P)⩾1, –log10(P) ⩾2, –log10(P) ⩾3 corresponding to P⩽1, P⩽0.1, P⩽0.01, P⩽0.001, respectively). Nominal P-values (–log10(P)) are plotted on the y-axis, and empirical quantiles (–log10(q), where q=1−ecdf(P)) are plotted on the x-axis. To assess polygenic effects below the standard GWAS significance threshold, we focused the Q-Q plots on SNPs with nominal –log10(P)<7.3 (corresponding to P>5 × 10−8). The same procedure was used for BD. The ‘enrichment' seen in the conditional Q-Q plots can be directly interpreted in terms of true discovery rate (TDR=1− FDR).29 This is illustrated in Figures 1b and 2b for each range of P-values in the pleiotropic traits (see Supplementary Information for details).

Bottom Line: We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS.In contrast, we found no genetic overlap between BD and MS.Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

View Article: PubMed Central - PubMed

Affiliation: 1] NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.

ABSTRACT
Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21,856) and multiple sclerosis (MS) (n=43,879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16,731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

No MeSH data available.


Related in: MedlinePlus