Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively approximately 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.

To evaluate evidence for de novo etiologies in schizophrenia, we sequenced at high coverage the exomes of families recruited from two populations with distinct demographic structure and history. We sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios. We observed in cases an excess of non-synonymous single nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance. We show that de novo mutations affect genes with diverse functions and developmental profiles but we also find a substantial contribution of mutations in genes with higher expression in early fetal life. Our results help define the pattern of genomic and neural architecture of schizophrenia.

Despite high heritability, a large fraction of cases with schizophrenia do not have a family history of the disease (sporadic cases). Here, we examine the possibility that rare de novo protein-altering mutations contribute to the genetic component of schizophrenia by sequencing the exome of 53 sporadic cases, 22 unaffected controls and their parents. We identified 40 de novo mutations in 27 patients affecting 40 genes including a potentially disruptive mutation in DGCR2, a gene removed Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms * Correspondence should be addressed to Maria Karayiorgou (mk2758@columbia.edu) or Joseph A. Gogos (jag90@columbia.edu). URLs: Picard (http://picard.sourceforge.net/) SAM tools (http://samtools.sourceforge.net/) PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) UCSC Table Browser (http://genome.ucsc.edu/cgi-bin/hgTables) The Human Splicing Finder (HSF, Version 2.4.1) software (http://www.umd.be/HSF/) R (www.r-project.org/) dbSNP v132 (ftp://ftp.ncbi.nlm.nih.gov/snp/organisms/human_9606/VCF/v4.0/00-All.vcf.gz) GATK VCF annotation file for hg19 (ftp://gatk-ftp:PH5UH7Pa@ftp.broadinstitute.org/refGene/refGene-big-table-hg19.txt.gz) Accession codes: Reference sequences are available from NCBI under the following accession codes: PLCL2, NM_001144382; WDR11, NM_018117; DPYD, NM_000110; OR4C46, NM_001004703; UGT1A3, NM_019093; FAM3D, NM_138805; KLF12, NM_007249; ADCY7, NM_001114; GPR153, NM_207370; PML, NM_002675; SLC26A8, NM_052961; CCDC108, NM_152389; TRAK1, NM_001042646; FASTKD5, NM_021826; DGCR2, NM_005137; ACOT6, NM_001037162; PITPNM1, NM_001130848; NPRL2, NM_006545; MAGEC1, NM_005462; TRRAP, NM_003496; COL3A1, NM_000090; GIF, NM_005142; TEKT5, NM_144674; THBS1, NM_003246; PAG1, NM_018440; RGS12, NM_002926; SAP30BP, NM_013260; ZNF530, NM_020880; MTOR, NM_004958; INPP5A, NM_005539; EDEM2, NM_001145025; CELF2, NM_001083591; SLC26A7, NM_134266; VPS35, NM_018206; ADAMTS3, NM_014243; GPR115, NM_153838; SPATA5, NM_145207; RB1CC1, NM_014781; LAMA2, NM_000426; ESAM, NM_138961 AUTHOR CONTRIBUTIONS BX, JAG and MK designed the study, interpreted the data and prepared the manuscript; BX developed the analysis pipeline and had the primary role in analysis and validation of sequence data; JLR collected the samples and was the primary clinician on the project; SL and BP performed exome library construction, capture and sequencing; PD contributed to the analysis of the data; BB contributed to the primary sequence data analysis; SL supervised the sequencing project at HudsonAlpha Institute and contributed to the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. 8,9 . Pilot studies in patients with SCZ focusing on specific synaptic genes identified a small number of putative de novo mutations 10 . However, the full contribution of rare de novo SNVs and in/d...

Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P = 0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P = 0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.