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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
JAMA Psychiatry. Author manuscript; available in PMC 2013 August 23.
Published in final edited form as:
PMCID: PMC3750982

A rare deletion at distal 16p11.2 is implicated in schizophrenia



Large genomic copy number variations (CNVs) have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.


To detect novel CNVs increasing susceptibility to schizophrenia, utilizing two ethnically homogeneous discovery cohorts and replication in large samples.


Genetic association study of microarray data.


DNA samples were collected at nine sites from different countries.


Two discovery cohorts were comprised of: a) 790 cases (schizophrenia and schizoaffective disorder) and 1347 controls of Ashkenazi Jewish descent; and b) 662 trios (offspring affected with schizophrenia or schizoaffective disorder) from Bulgaria. Replication datasets consisted of 12,398 cases and 17,945 controls.

Main outcome measure

Statistically increased rate of specific CNVs in cases versus controls.


One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 out of 13,850 cases (0.094%) and in 3 out of 19,954 controls (0.015%), Fisher Exact p = 0.0014; OR = 6.25 (95%CI = 1.78 – 21.93).


Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains nine genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional eight genes. Our findings add a new locus to the list of CNVs that increase risk to develop schizophrenia.


Uncovering the genetic factors underlying schizophrenia (SZ) has proven difficult despite heritability estimates of up to 80% 1. Copy number variants (CNVs) at several loci show consistently replicated evidence for association with SZ 2, 3. These CNVs are individually very rare, are not fully penetrant, and are found cumulatively in ~2% of SZ cases; therefore, large samples were required to establish their association. Given their low baseline frequency, it is likely that further CNV susceptibility loci have yet to be discovered.

In the present study, we report the identification of a CNV locus at distal 16p11.2 that increases risk for SZ. Findings pointing to a possible association between this locus and SZ were obtained independently by two teams of investigators. During the process of obtaining replication data, the two groups became aware of each other’s work and decided to combine results from their discovery and replication cohorts. Using highresolution microarrays, one group (from New York and Israel) examined a SZ case-control cohort from the Ashkenazi Jewish (AJ) population, while the other group (from Cardiff, UK) examined a cohort of parent-offspring trios from Bulgaria (BG). Because of the need for large-scale replication, we contacted research groups worldwide willing to share raw data from microarray-based CNV studies in cohorts of SZ and control individuals, and obtained data from a total of ~34,000 individuals.


Bulgarian Trios sample (BG)

Sample description

The final sample (after QC) consisted of 662 Bulgarian offspring with all their parents, in 638 families (615 families with one offspring, 22 with two offspring and one with three). Details on this cohort have been previously described4, but that previous publication only reported on de novo CNVs; here we report on the transmitted CNVs in this cohort. This cohort does not include patients with severe developmental disorders (all probands had attended mainstream schools, from which people with known intellectual disability were excluded). Diagnoses were made according to DSM-IV criteria 5, using a SCAN 6 interview and review of hospital discharge summaries. We included patients with schizophrenia or schizoaffective disorder. Concomitant medical conditions were not systematically assessed, except as related to psychiatric diagnosis. The CNVs found in the parents of each trio but not transmitted to the affected offspring comprised the “pseudocontrol” population listed in Table 1 under “controls”.

Table 1
CNVs at 16p11.2 in the discovery and replication sets

Genotyping and Quality Control (QC)

All samples were genotyped on Affymetrix 6.0 arrays at the Broad Institute, USA. Analysis was performed using Genotyping Console 4.0 software, one batch at a time, with each batch containing 70–90 arrays. QC included removal of CNVs if they were from the X or Y chromosome, less than 15kb, covered by less than 15 probes or a probe density (size/probe number) greater than 7500bp. PLINK v1.07 7 was used to exclude CNVs if 50% or more of their length was covered by a segmental duplication (SD). CNV loci with a frequency greater than 1% were excluded. Individuals with multiple large duplicate CNVs on the same chromosome were excluded, as these are likely to be artifacts 8. Samples were also removed if their total number of CNVs was very high and constituted an outlier for the distribution within that sample (>50 CNVs for this experiment).

For additional QC of the Bulgarian trios we used a modification of the MeZOD algorithm proposed by McCarthy et al 2009 9 and described in detail in Kirov et al., 2012 4. A Z-Score is the median of the standardised Log2 ratios for all probes within a specified chromosomal region. Through comparison of all individual Z-Scores for a given region, true CNVs are represented as outliers from the Z-Scores normal distribution. We show the distribution of the z-scores for the 16p11.2 distal region in the eSupplement (eFigure 1), which demonstrate that the only outliers for this region are the two probands with deletions, and their parents.

Ashkenazi Jewish sample (AJ)

Sample description

Case (n=1156) and control (n=2279) samples were selected from an Ashkenazi Jewish repository (Hebrew University Genetic Resource, HUGR, Patients for discovery analysis were recruited from hospitalized inpatients at seven medical centres in Israel. All diagnoses were assigned after direct interview using the structured clinical interview (SCID) 10, a questionnaire with inclusion and exclusion criteria, and cross-references to medical records. Chronic medical disorders and conditions were recorded based on both patient report and hospital records. The inclusion criteria specified that subjects had to be diagnosed with SZ or schizoaffective disorder by DSM-IV criteria 5, that all four grandparents of each subject were reported to be of Ashkenazi Jewish ethnic origin, and that each subject or the subject’s legal representative has signed the informed-consent form. Exclusion criteria included psychotic disorder due to a general medical condition, substance-induced psychotic disorder, pervasive developmental disorders, or any Cluster A (schizotypal, schizoid, or paranoid) personality disorder. Samples from healthy Ashkenazi individuals were collected from volunteers at the Israeli Blood Bank; these subjects were not psychiatrically screened but reported no chronic disease and were taking no medication at the time of blood draw. Corresponding institutional review boards and the National Genetic Committee of the Israeli Ministry of Health approved the studies. All samples were fully anonymized immediately after collection and subsequently, genomic DNA was extracted from blood samples through use of the Nucleon kit (Pharmacia). Genotyping and analyses were performed under protocols approved by the Institutional Review Board of the North Shore-LIJ Health System.

Genotyping and Quality Control (QC)

Genotyping was performed with Illumina HumanOmni1-Quad arrays according to manufacturers’ specifications for ~ 1.4 million genome wide markers (~900K SNPs and ~500K CNV intensity probes). SNPs were filtered on the following basis: call rate < 98%, minor allele frequency < 0.02 and Hardy-Weinberg exact test P < 0.000001 in controls. Samples were filtered based on genotype quality control filtration (sample call rate < 97 %, gender mismatch) and examined for cryptic identity and first- or second-degree relatedness using pairwise identity-by-decent (IBD) estimation (PI_HAT) in PLINK 7 with 128,403 LD pruned (r2 > 0.2) genome wide SNPs. Samples were excluded based on PI_Hat > 0.125; the individual with the lower call rate from each control/control or case/case pair was excluded, and controls were excluded from case/control pairs. The remaining samples were further examined for underlying population stratification using Principal Component Analysis (PCA) with Ancestry Informative Markers (AIMs) specific for the Ashkenazi Jewish population 11. Samples with PCA results suggestive of one or more non-AJ grandparents were identified as outliers based on first principal component score > 0.01 and were excluded from further analysis (eSupplement, eFigure2). After quality control based on SNP markers, the dataset contained 2544 samples comprised of 904 cases (573 male and 331 female) and 1640 controls (1216 male and 424 female) genotyped on 762,372 high-quality SNPs with 99.8 % overall call rate.

CNV calls and validation

Normalization and log ratio data calculation for 904 cases and 1640 controls were performed using Illumina GenomeStudio. The resulting log2 R ratios (LRR) and B-allele frequencies (BAF) were used to identify CNVs on autosomes for each subject. We used variations of three algorithms for CNV detection: PennCNV 8, QuantiSNP 12 and cnvPartition ( QuantiSNP and PennCNV are based on Hidden markov model (HMM) and cnvPartition is based on bivariate Gaussian distribution as implemented at Illumina GenomeStudio (

Following the methods of Need et al., (2009) 13 and Sanders et al. (2011) 14, we excluded any individuals with pennCNV threshold of LogR standard deviation (LRR_SD) ≥ 0.30, BAF drift ≥ 0.002, and/or Waviness factor (WF) deviating from 0 by > 0.04. Individuals containing > 500 CNVs (before filtration described below) were also excluded from the analysis. The final dataset contains 790 cases and 1347 controls.

We further excluded CNV calls based on QC thresholds recommended by each of the respective algorithms. Thus, CNV calls were excluded from further analysis if the Log Bayes Factor was ≤ 10 in QuantiSNP, confidence threshold ≤ 35 in cnvPartition, or default QC parameters in PennCNV were not obtained.

Following the QC steps all the CNV calls were merged using CNVision program 14 The final rare CNV calls were made based on consensus calls from all three algorithms (with no more than 25% of the length drawn from one algorithm only), with the following filtration criterion: ≥ 20 probes, ≥ 100kb in size, and <1% frequency in the total sample. CNVs of the same type (i.e., deletion or duplication) that were separated by ≤3 probes were merged into one contiguous segment as recommended by Vacic et al., 2011 15. All CNVs were annotated using CNVision. Based on previous findings in SZ and other neuropsychiatric disorders16, purely intergenic CNVs were excluded.

Replication samples

Evidence for replication of the findings was obtained from seven case-control samples recruited and genotyped by other teams from the USA, Europe and Japan. These comprised 12,398 cases and 17,945 controls genotyped with high-resolution arrays. Details on the samples, genotyping platforms and QC used by these teams are detailed in the eSupplement, Section 1. The minimally affected region was covered well by all arrays used by the other teams (eFigure 3).

All coordinates in this paper are based on the human genome build NCBI36/hg18.


After stringent quality control procedures, 790 cases and 1347 controls from the AJ cohort, and 662 probands from 638 BG families were examined for rare, large CNVs. Replication was sought in other case-control datasets for any CNVs that were observed in at least two cases and no controls (for the AJ cohort) and transmitted at least twice with no non-transmissions in the BG trios cohort. Several relevant CNVs were found in the two discovery datasets at loci already reported to increase risk to develop SZ, but as they are already known susceptibility factors, we only list them in the eSupplement eTable 4. In the AJ cohort, CNVs at two additional loci were observed in two cases and no controls. These were at chromosome 6q14.3 (hg18 coordinates: 85.25–85.58Mb) and 7q33 (133.39–133.50Mb), but replication evidence was not observed. No other CNV of this type was supported by replication evidence in the BG data (apart from the 16p11.2 deletion). The lists of all rare and large (>100kb) CNVs, in the two samples, that intersected genes, are available as eSupplement files (AJ_SZ_CNVs_over_100kb.xls and BG_SZ_trios_CNVs_over_100kb.xls).

The only CNV of interest that overlapped between the two discovery samples was a deletion at the distal region of 16p11.2, with a minimal common region between 28.73–28.95Mb (build 36, hg18). This region intersects nine genes and is flanked by two SD blocks (Figure 1). It does not overlap the known 16p11.2 locus at 29.56–30.11Mb that has been implicated in SZ 9, 16, autism 14, 17 and developmental delay 18. Deletions at this locus were found in two cases (and no controls) from the AJ cohort and two offspring from the BG samples, both transmitted from mothers (there were no parents who did not transmit this CNV). Duplications at this locus were observed in one AJ control and in one BG parent (who transmitted it to an affected offspring).

We sought evidence for association between this deletion with SZ in seven independent case-control cohorts (12,398 cases and 17,945 controls) where we had access to the raw data (Table 1 and eSupplement, Section 1). Deletions overlapping this region were observed in an additional nine cases and three controls (Fisher exact for the replication sample p = 0.018, one-tailed; OR = 4.35 (95% CI = 1.18 - 16.06). Combining the discovery and replication cohorts, we found 13 deletions among 13,850 cases (0.094%) and three among 19,954 controls (0.015%) (two-tailed Fisher exact test p = 0.0014, OR = 6.25, 95%CI = 1.78 - 21.93). The positions of the CNVs are shown in Figure 1. There was no excess of duplications in cases at distal 16p11.2.

The minimal common region for all deletions reported in Table 1 encompasses nine genes within a 220kb interval flanked by blocks of SD (Figure 1). Some CNVs extend over the SDs, (however, we note that no CNV in the 16p11.2 region was excluded on the basis of >50% overlap with SD). Different breakpoints that extend over the flanking SD regions (but do not reach the telomeric region that is free of SDs) are more likely to reflect the different coverage of arrays (eSupplement eFigure 3) and/or the problems of calling CNVs over repetitive regions, rather than to have different pathogenicity, especially as these regions have fewer genes. Seven deletions cover an additional region of unique DNA sequence, at the telomeric side (very left on Figure 1, the interval free of SDs), that contains further genes. Evidence for pathogenicity of the seven CNVs that extended over the telomeric region was nearly as strong as for the implicated critical region (7/13,850 cases vs. 0/19,954 controls, two-tailed Fisher exact test p = 0.0019). However the critical “distal 16p11.2 region” remains the more likely candidate due to its confirmed involvement in other neurodevelopmental disorders (see Discussion), and the lack of isolated CNVs in the smaller telomeric region. Out of the three controls with deletions, one (in the Swedish dataset) was recruited at the age of 45, had diabetes type 2, and high blood pressure, but no other medical or psychiatric problems. No further information is available on the two anonymized controls from the WTCCC2/Irish dataset: one is from the British Blood Transfusion service (therefore presumably healthy), and the other one from the 1958 cohort.

Importantly, the new “distal” locus is approximately 600kb telomeric from the previously implicated “proximal” 16p11.2 CNV (29.56–30.11Mb) 9. CNVs at “proximal” 16p11.2 have been shown to increase risk for SZ, autism, and developmental delay when duplicated 5,16, and for autism and developmental delay when deleted 9, 14, 18. None of the CNVs in our study extend over the “proximal” region (Figure 1).

We have previously demonstrated that the known SZ-associated CNVs have high mutation rates and that strong selection pressure operates against them 24. We are able to estimate the de novo rate for this deletion at 25% based on the current study (two transmitted deletions and no information on inheritance in the other subjects) and four available datasets with a total of 5 de novo occurrences out of 20 events with a known inheritance 1922 (eSupplement Section 7). This approximates to a selection pressure of 0.25. In line with this we observe the two BG proband deletions to be found on different haplotypes, and therefore very likely to be independent mutations.

Phenotypic data, where available, indicate a spectrum of typical presentations of SZ with no evidence for intellectual disability, or a specific clinical profile (eTable 2). This is similar to the lack of specific clinical presentations reported for the other large CNVs implicated in neurodevelopmental disorders 2, 14, 19. The possible exception is the presence of two individuals with obesity and two with type 2 diabetes (plus one control with type 2 diabetes) in line with previous reports, (see Discussion). In addition to the 13 cases listed in Table 1 and eTable 2, we note that the brother of one case (in the Japanese sample) carries the same deletion and is also affected with SZ. Further probands had positive family histories of SZ, but we do not know if their affected relatives also carry the deletion. Although the transmission status of the CNVs is only available for the BG cohort, we further note that both deletions were transmitted maternally.


Several lines of evidence from the literature support the distal 16p11.2 deletion as a true SZ-associated CNV locus. The deletion has been implicated in developmental delay and other clinical phenotypes 18, 19, 20 (details in eTable 1), similar to other SZ-associated CNVs 2, 3, 9. Briefly, Cooper et al. (2011) 18 reported a very similar increased rate of 0.1% (15/15,767) for this deletion in children with intellectual disability, autism spectrum disorders and congenital malformations, that were referred for genetic testing, compared with a control rate of 0.01% (1/8329). Similar rates were found in another large study on patients with developmental delay and a range of other abnormal phenotypes 19: 31/23,084 cases (0.13%) and 1/7700 controls (0.01%). Interestingly, out of the six cases in that study, for whom detailed clinical information was available, one had autism, behavioral problems/ADHD and SZ, another one had behavioral problems/ADHD and bipolar disorder, and a third one had autism. Four of these six cases were overweight and all six had developmental delay. Moreover, additional telomeric extension of the deletion (to approx. 28.4Mb) was present in 9 of the 31 cases and was never observed in controls. Similarly, in our study, 7 of the 13 of the cases demonstrated this telomeric extension, whereas this was not seen in the controls. We note that the controls used in these studies partially overlap ours, so these control rates are not independent, (eSupplement Section 4, eTable 1). Additional published reports of distal 16p11.2 deletions include five patients from two separate families 21, all of whom have developmental delay and behavioral problems, and one child out of 4284 patients with mental retardation 22.

Distal 16p11.2 deletions have also been shown to be enriched in patients with severe early-onset obesity (3/300 = 1%) compared to unscreened population controls (2/7366 = 0.03%) 20, consistent with the findings in the study by Bachmann-Gagescu et al 19, discussed above. It was postulated that the most likely obesity candidate within the distal 16p11.2 region is SH2B1, as this gene plays a role in the regulation of body weight and glucose homeostasis in mice 23. Two of our cases were obese/overweight, and two cases and one control had type 2 diabetes, (consistent with being overweight although this information is not available). However, one carrier (from Japan) had documented evidence of normal weight, and several did not have recorded evidence of obesity despite being drawn from cohorts that were assessed for this and other medically-relevant phenotypes.

Considerable heterogeneity of phenotypic expression has been reported for most large rare CNVs implicated in SZ, with carriers often manifesting non-psychotic phenotypes including intellectual disability, autism, epilepsy, obesity, and cardiac disorders 2,16. Pleiotropy appears to also be the case for distal 16p11.2 deletions, possibly due to the presence of multiple genes within the deleted region.

Clinical presentations for distal 16p11.2 deletion carriers are unremarkable for SZ, with diagnoses ranging across all major subtypes: paranoid, catatonic, undifferentiated and schizoaffective. Age of SZ onset for deletion carriers ranges from 15–30 (mean = 23.4), with no clear evidence for early onset. Two parents who transmitted the deletions to probands did not have psychotic disorders, although one had a mood disorder. Out of the three controls who carry the deletion, one (from Sweden) did not report psychiatric problems at the age of 45, when interviewed, past the usual accepted age for the period of risk for SZ. Of the other two controls, one had also passed through the risk period (from the 1958 cohort, examined at the age of 44–45, see eSupplement) and the third one, a blood donor, is presumably healthy and not on any medication. These observations indicate that this CNV does not have full penetrance, similar to most other CNVs implicated in SZ. None of the carriers had any other SZ-associated CNVs.

Mutations in several of the nine genes within the critical region of distal 16p11.2 have been implicated in neurological diseases: homozygous mutations in the gene TUFM have been described in infants with fatal encephalopathy 25; ATP2A1 is implicated in Brody disease in which patients are unable to relax their muscle during exercise 26, and its homologue, ATP2A2 has been implicated in neuropsychiatric phenotypes 27; ATXN2L (although unknown in function) encodes a protein belonging to the spinocerebellar ataxia family. The remaining genes are either involved in immunity, insulin and leptin signaling (SH2B1) or are of unknown function. In addition to the nine genes in the minimal critical region, the larger CNVs with telomeric extensions include eight additional deleted genes (seven of them in DNA region that is free of SDs, Figure 1), possibly increasing the pathogenicity of these larger CNV. Most notable among these eight genes is CLN3, where recessive mutations are associated with Batten disease, characterized by childhood-onset neurodegeneration 28. Moreover, CLN3 is the only gene in either the minimal or the extended region that is implicated in synaptic function based on Gene Ontology annotation. Our previous study of de novo CNVs indicated an enrichment of such genes in SZ-related events, however CLN3 is not among the post-synaptic density (PSD) genes, implicated in that study 4. Additional evidence from animal knockout models may help disentangle the contributions of each of these genes to the observed range of phenotypes.

In conclusion, we have obtained strong evidence for the role of a new CNV locus in SZ. Similar to other such loci, it is very rare and increases risk for other neurodevelopmental phenotypes.

Figure 1
Microdeletions at 16p11.2 distal region in the current study

Supplementary Material

Supplementary Information


Work at Cardiff University was funded by Medical Research Council (MRC) Programme (Ref G0800509) and Centre Grants, the National Institutes of Mental Health (USA) (CONTE: 2 P50 MH066392–05A1), and a grant from the EU (EU-GEI). Genotyping was funded by multiple grants to the Stanley Center for Psychiatric Research at the Broad Institute from the Stanley Medical Research Institute, The Merck Genome Research Foundation, and the Herman Foundation. The Zucker Hillside work was supported by the North Shore-LIJ Health System Foundation and the National Institutes of Health (RC2 MH089964 and R01 MH084098 to T.L; P50 MH080173 to A.K.M and P30 MH090590 to J.M.K).

MGS data collection was supported by National Institute of Mental Health (NIMH) R01 grants MH67257, MH59588, MH59571., MH59565, MH59587, MH60870, MH59566, MH59586, MH61675, MH60879, and MH81800, NIMH U01 grants MH46276, MH46289, MH46318, MH79469 and MH79470. Support is acknowledged from NARSAD (National Alliance for Research on Schizophrenia and Depression) Young Investigator Awards (to J.D. and A.R.S.), the Genetic Association Information Network (GAIN), the Paul Michael Donovan Charitable Foundation, and the Walter E. Nichols, M.D., and Eleanor Nichols endowments (Stanford University). Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT (S. Gabriel and D. B. Mirel) with support from grant U54 RR020278 from the National Center for Research Resources.

The German study was supported by the German Federal Ministry of Education and Research (BMBF), within the context of the Integrated Genome Research Network (IG) MooDS (grants 01GS08144 and 01GS08147). Control data were provided by the community-based studies of PopGen, KORA, the Heinz Nixdorf Recall (HNR) study, and MooDS.

Genotyping of WTCCC2 samples was funded by the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z). The British 1958 Birth Cohort DNA collection was funded by the UK Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and the UK National Blood Service controls by the Wellcome Trust.

The Japanese cohort was supported in part by research grants from the Japan Ministry of Education, Culture, Sports, Science and Technology; the Ministry of Health, Labor and Welfare; the Core Research for Evolutional Science and Technology; and the Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation).

Funding sources did not have any role in the design of study and approval of manuscript.

The authors report no relevant financial interests to disclose.


Author Contributions

SG, ER, AD, MCO’D, TL, and GK wrote the manuscript. TL, AD, JMK, GK and AKM conceptualized and designed the study. SG, ER, TL, and GK performed the primary analyses, interpreted the genome wide data, and take responsibility for the integrity of the data and the accuracy of the data analysis. JR contributed in statistical analyses. All other authors contributed to collection, phenotyping, and genotyping of samples. All authors reviewed, edited, and approved the final manuscript.


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