No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia

Douglas M Ruderfer; Elaine T Lim; Giulio Genovese; Jennifer L Moran; Christina M Hultman; Patrick F Sullivan; Steven A McCarroll; Peter Holmans; Pamela Sklar; Shaun M Purcell

doi:10.1038/ejhg.2014.228

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia

Eur J Hum Genet. 2015 Apr;23(4):555-7. doi: 10.1038/ejhg.2014.228. Epub 2014 Nov 5.

Authors

Affiliations

¹ 1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA [3] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁶ 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁷ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁸ 1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ 1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA [3] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [4] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Abstract

Recessive inheritance of gene disrupting alleles, either through homozygosity at a specific site or compound heterozygosity, have been demonstrated to underlie many Mendelian diseases and some complex psychiatric disorders. On the basis of exome sequencing data, an increased burden of complete knockout (homozygous or compound heterozygous) variants has been identified in autism. In addition, using single-nucleotide polymorphism microarray data, an increased rate of homozygosity by descent, or autozygosity, has been linked to the risk of schizophrenia (SCZ). Here, in a large Swedish case-control SCZ sample (11 244 individuals, 5079 of whom have exome sequence data available), we survey the contribution of both autozygosity and complete knockouts to disease risk. We do not find evidence for association with SCZ, either genome wide or at specific loci. However, we note the possible impact of sample size and population genetic factors on the power to detect and quantify any burden that may exist.

MeSH terms

Alleles
Case-Control Studies
Exome
Female
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
Genetics, Population
Heterozygote*
Homozygote
Humans
Logistic Models
Male
Polymorphism, Single Nucleotide*
Schizophrenia / diagnosis
Schizophrenia / genetics*
Sequence Analysis, DNA
Sweden
White People / genetics

Abstract

MeSH terms

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