Inherited L1 Retrotransposon Insertions Associated With Risk for Schizophrenia and Bipolar Disorder

Benjamin C Reiner; Glenn A Doyle; Andrew E Weller; Rachel N Levinson; Aditya M Rao; Emilie Davila Perea; Esin Namoglu; Alicia Pigeon; Gabriella Arauco-Shapiro; Cyndi Shannon Weickert; Gustavo Turecki; Richard C Crist; Wade H Berrettini

doi:10.1093/schizbullopen/sgab031

Inherited L1 Retrotransposon Insertions Associated With Risk for Schizophrenia and Bipolar Disorder

Schizophr Bull Open. 2021 Jul 14;2(1):sgab031. doi: 10.1093/schizbullopen/sgab031. eCollection 2021 Jan.

Affiliations

¹ Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Schizophrenia Research Laboratory, Neuroscience Research Australia & School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
³ Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY, USA.
⁴ McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Canada.

Abstract

Studies of the genetic heritability of schizophrenia and bipolar disorder examining single nucleotide polymorphisms (SNPs) and copy number variations have failed to explain a large portion of the genetic liability, resulting in substantial missing heritability. Long interspersed element 1 (L1) retrotransposons are a type of inherited polymorphic variant that may be associated with risk for schizophrenia and bipolar disorder. We performed REBELseq, a genome wide assay for L1 sequences, on DNA from male and female persons with schizophrenia and controls (n = 63 each) to identify inherited L1 insertions and validated priority insertions. L1 insertions of interest were genotyped in DNA from a replication cohort of persons with schizophrenia, bipolar disorder, and controls (n = 2268 each) to examine differences in carrier frequencies. We identified an inherited L1 insertion in ARHGAP24 and a quadallelic SNP (rs74169643) inside an L1 insertion in SNTG2 that are associated with risk for developing schizophrenia and bipolar disorder (all odds ratios ~1.2). Pathway analysis identified 15 gene ontologies that were differentially affected by L1 burden, including multiple ontologies related to glutamatergic signaling and immune function, which have been previously associated with schizophrenia. These findings provide further evidence supporting the role of inherited repetitive genetic elements in the heritability of psychiatric disorders.

Keywords: L1Hs/REBELseq.