TY - JOUR

T1 - Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate

AU - Andreassen, Ole A

AU - Thompson, Wesley K

AU - Schork, Andrew J

AU - Ripke, Stephan

AU - Mattingsdal, Morten

AU - Kelsoe, John R

AU - Kendler, Kenneth S

AU - O'Donovan, Michael C

AU - Rujescu, Dan

AU - Werge, Thomas

AU - Sklar, Pamela

AU - Roddey, J Cooper

AU - Chen, Chi-Hua

AU - McEvoy, Linda

AU - Desikan, Rahul S

AU - Djurovic, Srdjan

AU - Dale, Anders M

AU - Psychiatric Genomics Consortium (PGC)

PY - 2013/4

Y1 - 2013/4

N2 - Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q-Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders.

AB - Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q-Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders.

U2 - 10.1371/journal.pgen.1003455

DO - 10.1371/journal.pgen.1003455

M3 - Journal article

C2 - 23637625

VL - 9

SP - e1003455

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 4

ER -