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Meta-Analysis
, 50 (3), 381-389

Common Schizophrenia Alleles Are Enriched in Mutation-Intolerant Genes and in Regions Under Strong Background Selection

Antonio F Pardiñas  1 Peter Holmans  1 Andrew J Pocklington  1 Valentina Escott-Price  1 Stephan Ripke  2   3 Noa Carrera  1 Sophie E Legge  1 Sophie Bishop  1 Darren Cameron  1 Marian L Hamshere  1 Jun Han  1 Leon Hubbard  1 Amy Lynham  1 Kiran Mantripragada  1 Elliott Rees  1 James H MacCabe  4 Steven A McCarroll  5 Bernhard T Baune  6 Gerome Breen  7   8 Enda M Byrne  9   10 Udo Dannlowski  11 Thalia C Eley  7 Caroline Hayward  12 Nicholas G Martin  13   14 Andrew M McIntosh  15   16 Robert Plomin  7 David J Porteous  12 Naomi R Wray  9   10 Armando Caballero  17 Daniel H Geschwind  18 Laura M Huckins  19 Douglas M Ruderfer  19 Enrique Santiago  20 Pamela Sklar  19 Eli A Stahl  19 Hyejung Won  18 Esben Agerbo  21   22 Thomas D Als  21   23   24 Ole A Andreassen  25   26 Marie Bækvad-Hansen  21   27 Preben Bo Mortensen  21   22   23 Carsten Bøcker Pedersen  21   22 Anders D Børglum  21   23   24 Jonas Bybjerg-Grauholm  21   27 Srdjan Djurovic  28   29 Naser Durmishi  30 Marianne Giørtz Pedersen  21   22 Vera Golimbet  31 Jakob Grove  21   23   24   32 David M Hougaard  21   27 Manuel Mattheisen  21   23   24 Espen Molden  33 Ole Mors  21   34 Merete Nordentoft  21   35 Milica Pejovic-Milovancevic  36 Engilbert Sigurdsson  37 Teimuraz Silagadze  38 Christine Søholm Hansen  21   27 Kari Stefansson  39 Hreinn Stefansson  39 Stacy Steinberg  39 Sarah Tosato  40 Thomas Werge  21   41   42 GERAD1 ConsortiumCRESTAR ConsortiumDavid A Collier  7   43 Dan Rujescu  44   45 George Kirov  1 Michael J Owen  46 Michael C O'Donovan  47 James T R Walters  48
Collaborators, Affiliations
Meta-Analysis

Common Schizophrenia Alleles Are Enriched in Mutation-Intolerant Genes and in Regions Under Strong Background Selection

Antonio F Pardiñas et al. Nat Genet.

Erratum in

  • Publisher Correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
    Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, Legge SE, Bishop S, Cameron D, Hamshere ML, Han J, Hubbard L, Lynham A, Mantripragada K, Rees E, MacCabe JH, McCarroll SA, Baune BT, Breen G, Byrne EM, Dannlowski U, Eley TC, Hayward C, Martin NG, McIntosh AM, Plomin R, Porteous DJ, Wray NR, Caballero A, Geschwind DH, Huckins LM, Ruderfer DM, Santiago E, Sklar P, Stahl EA, Won H, Agerbo E, Als TD, Andreassen OA, Bækvad-Hansen M, Mortensen PB, Pedersen CB, Børglum AD, Bybjerg-Grauholm J, Djurovic S, Durmishi N, Pedersen MG, Golimbet V, Grove J, Hougaard DM, Mattheisen M, Molden E, Mors O, Nordentoft M, Pejovic-Milovancevic M, Sigurdsson E, Silagadze T, Hansen CS, Stefansson K, Stefansson H, Steinberg S, Tosato S, Werge T; GERAD1 Consortium; CRESTAR Consortium, Collier DA, Rujescu D, Kirov G, Owen MJ, O'Donovan MC, Walters JTR. Pardiñas AF, et al. Nat Genet. 2019 Jul;51(7):1193. doi: 10.1038/s41588-019-0450-7. Nat Genet. 2019. PMID: 31160808

Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Conflict of interest statement

Competing interests

D.A.C. is a full-time employee and stockholder of Eli Lilly and Company. The remaining authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Manhattan plot of schizophrenia GWAS associations
Associations are shown from the meta-analysis of CLOZUK and an independent PGC dataset (n = 105,318; 40,675 cases and 64,643 controls). The 145 genome-wide significant loci are highlighted in green. The red horizontal line indicates the genome-wide statistical significance threshold (P = 5×10−8).
Fig. 2
Fig. 2. Partitioned heritability analysis of gene sets in schizophrenia
a, Heritability of genomic partitions and the six conditionally independent (‘significant’) gene sets (Table 2). The radius of each segment indicates the degree of enrichment, while the arc (angle of each slice) indicates the percentage of total SNP-based heritability explained. No relative enrichment (enrichment = 1) is shown by the dashed red line (and depletion equates to enrichment <1, inside red line). b, Heritability of the significant CNS gene sets dissected by their overlap with LoF-intolerant genes. Whiskers represent heritability or enrichment standard errors. Asterisks indicate the significance of each heritability enrichment (*P≤0.05, **P≤0.01, ***P≤0.001).

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