Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes.
Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies.
Center for Quantitative Genetics and Genomics, Department of Molecular Biology and Genetics, Aarhus University, 8830 Tjele, Denmark iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus, Denmark iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000 Aarhus, Denmark palle.d.rohde@mbg.au.dk.
Palle Duun
0000-0003-4347-8656
PD
Rohde
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus, Denmark iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000 Aarhus, Denmark Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Ditte
D
Demontis
Center for Quantitative Genetics and Genomics, Department of Molecular Biology and Genetics, Aarhus University, 8830 Tjele, Denmark.
Beatriz Castro Dias
BC
Cuyabano
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000 Aarhus, Denmark iSEQ, Centre for Integrative Sequencing, Aarhus University, 8000 Aarhus, Denmark Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Anders D
AD
Børglum
Center for Quantitative Genetics and Genomics, Department of Molecular Biology and Genetics, Aarhus University, 8830 Tjele, Denmark.
Peter
P
Sørensen
D003198:Computer Simulation; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014801:Vitamin A / Q000235:genetics* / Q000378:metabolism
D014801:Vitamin A
GBLUP; association test; complex disease; schizophrenia; set test