Testing the antagonistic pleiotropy model of schizophrenia susceptibility by analysis of DAOA, PPP1R1B, and APOL1 genes.
Schizophrenia is a common disease associated with reduced fertility. Therefore, the existence of common susceptibility alleles not removed by natural selection may be considered an evolutionary paradox. The antagonistic pleiotropy model, proposed to explain this paradox, states that an allele may be common because of its overall selective advantage, in spite of deleterious effects on specific traits. Recent work on DAOA, PPP1R1B, and APOL1 suggests that these genes present common alleles associated to increase risk of schizophrenia but conferring an overall selective advantage, related to better cognitive performance (DAOA and PPP1R1B) or protection against pathogens (APOL1). To test if these genes fit the antagonistic pleiotropy model, we searched for recent natural selection at these loci applying the long-range haplotype test on data from the HapMap Project; and performed case-control association analysis in a well-powered sample, including 301 schizophrenic patients and 604 controls from Spain. For DAOA and PPP1R1B, we genotyped the Single-nucleotide polymorphisms (SNPs) needed to replicate previous associations, while for APOL1, we genotyped 15 tagSNPs, and seven putative functional SNPs. We did not detect evidence of recent natural selection. Furthermore, we did not find significant associations. Thus, these genes do not fit the antagonistic pleiotropy model.
Carrera
Noa
N
Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
Arrojo
Manuel
M
Paz
Eduardo
E
Ramos-Ríos
Ramón
R
Agra
Santiago
S
Páramo
Mario
M
Brenlla
Julio
J
Costas
Javier
J
D000328:Adult; D000368:Aged; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium / Q000502:physiology; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D013030:Spain
C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D002352:Carrier Proteins; C475071:DAOA protein, human; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; C497928:PPP1R1B protein, human