title: LINE1 insertions as a genomic risk factor for schizophrenia: Preliminary evidence from an affected family.
abstract: Recent studies show that human-specific LINE1s (L1HS) play a key role in the development of the central nervous system (CNS) and its disorders, and that their transpositions within the human genome are more common than previously thought. Many polymorphic L1HS, that is, present or absent across individuals, are not annotated in the current release of the genome and are customarily termed "non-reference L1s." We developed an analytical workflow to identify L1 polymorphic insertions with next-generation sequencing (NGS) using data from a family in which SZ segregates. Our workflow exploits two independent algorithms to detect non-reference L1 insertions, performs local de novo alignment of the regions harboring predicted L1 insertions and resolves the L1 subfamily designation from the de novo assembled sequence. We found 110 non-reference L1 polymorphic loci exhibiting Mendelian inheritance, the vast majority of which are already reported in dbRIP and/or euL1db, thus, confirming their status as non-reference L1 polymorphic insertions. Four previously undetected L1 polymorphic loci were confirmed by PCR amplification and direct sequencing of the insert. A large fraction of our non-reference L1s is located within the open reading frame of protein-coding genes that belong to pathways already implicated in the pathogenesis of schizophrenia. The finding of these polymorphic variants among SZ offsprings is intriguing and suggestive of putative pathogenic role. Our data show the utility of NGS to uncover L1 polymorphic insertions, a neglected type of genetic variants with the potential to influence the risk to develop schizophrenia like SNVs and CNVs. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts.
authors.forename: Guia
authors.initials: G
authors.lastname: Guffanti
authors.affiliation: Department of Infectious, Parasitic and Immune-Mediated Diseases, Italian National Institute of Health, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Gaudi
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts.
authors.forename: Torsten
authors.initials: T
authors.lastname: Klengel
authors.affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California.
authors.forename: James H
authors.initials: JH
authors.lastname: Fallon
authors.affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California.
authors.forename: Harry
authors.initials: H
authors.lastname: Mangalam
authors.affiliation: Division of Mathematics and Computer Science, Argonne National Laboratory, Lemont, Illinois.|Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Ravi
authors.initials: R
authors.lastname: Madduri
authors.affiliation: Division of Mathematics and Computer Science, Argonne National Laboratory, Lemont, Illinois.|Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Alex
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Department of Psychiatry, Columbia University Medical Center and New York State Psychiatric Institute, New York, New York.
authors.forename: Paula
authors.initials: P
authors.lastname: DeCrescenzo
authors.affiliation: Department of Psychiatry, Columbia University Medical Center and New York State Psychiatric Institute, New York, New York.
authors.forename: Emily
authors.initials: E
authors.lastname: Glovienka
authors.affiliation: SUNY Downstate, College of Medicine, Brooklyn, New York.
authors.forename: Janet
authors.initials: J
authors.lastname: Sobell
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts.
authors.forename: Claudia
authors.initials: C
authors.lastname: Klengel
authors.affiliation: SUNY Downstate, College of Medicine, Brooklyn, New York.
authors.forename: Michele
authors.initials: M
authors.lastname: Pato
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: SUNY Downstate, College of Medicine, Brooklyn, New York.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pato
authors.affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California.|Center for Autism Research and Treatment (CART), University of California, Irvine, California.|Center for Epigenetics and Metabolism, University of California, Irvine, California.
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
mesh_terms: D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D016366:Open Reading Frames; D010375:Pedigree; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA
keywords: LINE1; mobile elements; next-generation sequencing; retrotransposition; schizophrenia