Andreassen, Ole A

Bipolar Disorder and Schizophrenia Working Groups

Chen, Chi-Hua

Dale, Anders M

Desikan, Rahul S

Djurovic, Srdjan

Kelsoe, John R

Kendler, Kenneth S

Mattingsdal, Morten

McEvoy, Linda

O'Donovan, Michael C

Psychiatric Genomics Consortium (PGC)

Ripke, Stephan

Roddey, J Cooper

Rujescu, Dan

Schork, Andrew J

Sklar, Pamela

Thompson, Wesley K

Werge, Thomas

eScholarship - University of California

UC San DiegoUC San Diego Previously Published WorksTitleCorrection: Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate.Permalinkhttps://escholarship.org/uc/item/6kw2q0vxJournalPLoS genetics, 11(11)ISSN1553-7390AuthorsAndreassen, Ole AThompson, Wesley KSchork, Andrew Jet al.Publication Date2015-11-01DOI10.1371/journal.pgen.1005544 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaCORRECTIONCorrection: Improved Detection of CommonVariants Associated with Schizophrenia andBipolar Disorder Using Pleiotropy-InformedConditional False Discovery RateOle A. Andreassen, Wesley K. Thompson, Andrew J. Schork, Stephan Ripke,Morten Mattingsdal, John R. Kelsoe, Kenneth S. Kendler, Michael C. O'Donovan,Dan Rujescu, ThomasWerge, Pamela Sklar, The Psychiatric Genomics Consortium(PGC), Bipolar Disorder and Schizophrenia Working Groups, J. Cooper Roddey, Chi-Hua Chen, Linda McEvoy, Rahul S. Desikan, Srdjan Djurovic, Anders M. DaleIncorrect mathematical definition of the conjunction FDR in the section ‘Conjunctionstatistics—test of association with both phenotypes’Under the sub-heading of ‘Conjunction statistics—test of association with both phenotypes’in the ‘Materials and Methods’ section of the manuscript, there are errors in the mathematicaldefinition of the conjunction FDR. The authors have provided an updated version here withcorrections to the text in bold:In order to identify which of the SNPs were associated with schizophrenia and bipolar disor-der we used a conjunction FDR procedure similar to that described for p-value statistics inNichols et al. [45]. This minimizes the effect of a single phenotype driving the common associa-tion signal. Conjunction FDR is defined as the posterior probability that a given SNP is null foreither phenotype or both phenotypes simultaneously when the p-values for both phenotypesare as small or smaller than the observed p-values. Formally, conjunction FDR is given byFDRSCZ&BDðp1; p2Þ ¼ π0 F0ðp1; p2Þ=Fðp1; p2Þ þ π1 F1ðp1; p2Þ=Fðp1; p2Þ þ π2 F2ðp1; p2Þ=Fðp1; p2Þ; ð6Þwhere π0 is the a priori proportion of SNPs null for both SCZ and BD simultaneously andF0(p1, p2) is the joint null cdf, π1 is the a priori proportion of SNPs non-null for SCZ andnull for BD with F1(p1, p2) the joint cdf of these SNPs, and π2 is the a priori proportion ofSNPs non-null for BD and null for SCZ, with joint cdf F2(p1, p2). F(p1, p2) is the joint over-all mixture cdf for all SCZ and BD SNPs.Conditional empirical cdfs provide a model-free method to obtain conservative estimates ofEq (6). This can be seen as follows. Estimate the conjunction FDR byFDRSCZ&BD ¼ maxfFDRSCZjBD; FDRBDj SCZg ð7Þwhere FDRSCZ|BD and FDRBD| SCZ (the estimated conditional FDRs described above) are con-servative (upwardly biased) estimates of Eq. [5]. Thus, Eq (7) is a conservative estimate of max{p1/F(p1| p2), p2/F(p2|p1)} =max{p1F2(p2)/F(p1, p2), p2F1(p1)/F(p1, p2)}, with F1(p1) andF2(p2) the marginal non-null cdfs of SNPs for SCZ and BD, respectively. For enriched sam-ples, p-values will tend to be smaller than predicted from the uniform distribution, so thatPLOSGenetics | DOI:10.1371/journal.pgen.1005544 November 5, 2015 1 / 3OPEN ACCESSCitation: Andreassen OA, Thompson WK, SchorkAJ, Ripke S, Mattingsdal M, Kelsoe JR, et al. (2015)Correction: Improved Detection of Common VariantsAssociated with Schizophrenia and Bipolar DisorderUsing Pleiotropy-Informed Conditional FalseDiscovery Rate. PLoS Genet 11(11): e1005544.doi:10.1371/journal.pgen.1005544Published: November 5, 2015Copyright: © 2015 Andreassen et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.F1(p1) p1 and F2(p2) p2. Thenmaxfp1F2ðp2Þ=Fðp1; p2Þ; p2F1ðp1Þ=Fðp1; p2Þg ½π0 þ π1 þ π2maxfp1F2ðp2Þ=Fðp1; p2Þ; p2F1ðp1Þ=Fðp1; p2Þg ½π0p1p2 þ π1p2F1ðp1Þ þ π2p1F2ðp2Þ=Fðp1; p2Þ:Under the assumption that SNPs are independent if one or both are null, reasonable fordisjoint samples, this last quantity is precisely the conjunction FDR given in Eq (6). Thus,Eq (7) is a conservative model-free estimate of the conjunction FDR. We present a complemen-tary model-based approach to estimating conjunction FDR in the S1 Text.We assigned the conjunction FDR values by interpolation into a bi-directional two-dimen-sional look-up table (S3 Fig). All SNPs with conjunction FDR<0.05 (−log10(FDR)>1.3) withschizophrenia and bipolar disorder considered jointly are listed in Table 3 (after pruning),together with the corresponding z-scores and minor alleles. The z-scores were calculated fromthe p-values and the direction of effect was determined by the risk allele.Incorrect mathematical definition of the conjunction FDR in the ‘Conditional and Con-junction Local False Discovery Rate’ section of the S1 Text.There are also errors under the sub-heading ‘Conditional and Conjunction Local False Dis-covery Rate’ in the S1 Text. Please view the correct S1 Text here, with updates to the text in red.Supporting InformationS3 Fig. Conjunction FDR bi-directional 2-D Look-up table.(DOC)Table 3. Conjunction FDR; pleiotropic loci in SCZ and BD (SCZ&BD).locus SNP neighbor gene Chr A1 A2 conjfdr BD&SCZ z-score BD z-score SCZ1 rs2252865 RERE 1p36.23 T C 0.030 3.696 3.4942 rs4650608 IFI44 1p31.1 T C 0.043 3.289 3.7114 rs11205362 PRP3 1q21.1 G A 0.033 3.404 3.2628 rs9834970 TRANK1 3p22.2 C T 0.027 3.470 3.9659 rs4687657 ITIH4† 3p21.1 G T 0.028 3.787 3.78111 rs3134942 NOTCH4† 6p21.3 G T 0.048 3.251 3.57115 rs3757440 MAD1L1 7p22 A G 0.031 3.490 3.42520 rs10883757 TRIM8 10q24.3 C T 0.040 3.261 3.04622 rs1006737 CACNA1C† 12p13.3 A G 0.022 4.553 4.13726 rs961196 TTC7B 14q32.11 C T 0.044 3.618 2.96028 rs12708772 SHISA9 16p13.12 C T 0.044 3.294 2.95531 rs1800359 ZNF276 16q24.3 A G 0.035 3.329 3.16533 rs159788 BC039673 20p13 G A 0.034 3.411 -3.23235 rs381523 PPM1F 22q11.22 A G 0.045 3.220 3.166Independent complex or single gene loci (r2 < 0.2) with SNP(s) with a conjunctional FDR (conjFDR) < 0.05 in schizophrenia (SCZ) and bipolar disorder(BD). All SNPs with a conjFDR value < 0.05 (bidirectional association, i.e. association with SCZ given association with BD (condFDR< 0.05) andassociation with BD given association with SCZ (condFDR<0.05)) are listed and sorted in each LD block. We defined the most significant SNP in each LDblock based on the minimum conjFDR. All independent loci are listed consecutively, and the same locus number are used as in the condFDR < 0.05results (Table 1). Chromosome (Chr). Z-scores for each pleiotropic locus are provided, with minor allele (A1) and major allele (A2). All data were firstcorrected for genomic inflation. †Same locus identified in previous BD or SCZ genome-wide association studies.doi:10.1371/journal.pgen.1005544.t001PLOSGenetics | DOI:10.1371/journal.pgen.1005544 November 5, 2015 2 / 3S1 Text. Supporting statistical methods.(DOC)Reference1. Andreassen OA, ThompsonWK, Schork AJ, Ripke S, Mattingsdal M, Kelsoe JR, et al. (2013) ImprovedDetection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate. PLoS Genet 9(4): e1003455. doi:10.1371/journal.pgen.1003455 PMID: 23637625PLOS Genetics | DOI:10.1371/journal.pgen.1005544 November 5, 2015 3 / 3

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Correction: Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate.

Correction: Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate.

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