G2C::Genetics

Confirmed Rare Copy Number Variants Implicate Novel Genes in Schizophrenia

Gloria W. C. Tam1*, Louie N. van de Lagemaat1*, Richard R. Redon1, Mary P. Malloy2, Walter J. Muir2, Ben S. Pickard3, Karen E. Strathdee1, Mike D. R. Croning1, Ian J. Deary4, Douglas H.R. Blackwood2, Nigel P. Carter1 and Seth G. N. Grant1

Author email: sg3@sanger.ac.uk   * - These authors contributed equally to this work

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
  2. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh, EH10 5HF, UK
  3. Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, Glasgow G4 0NR
  4. Department of Psychology, University of Edinburgh, EH8 9JZ

Introduction

Detection of copy number deletion on chromosome 3 (arrowed) in the cell-recognition protein encoding gene <em>CHL1</em> in schizophrenic patient samples, as detected by whole-genome tiling path array CGH.

Detection of copy number deletion on chromosome 3 (arrowed) in the cell-recognition protein encoding gene <em>CHL1</em> in schizophrenic patient samples, as detected by whole-genome tiling path array CGH.

Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human cognitive disorders is one path that may ultimately give insight to the biochemical and cellular mechanisms of cognition. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics ( 19748074).

Here we identify genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Comparing this data with >3000 cases in the public domain confirms loci demonstrating a bias for mutation in schizophrenia.

In addition to identifying novel loci we found copy number variants in phosphodiesterase PDE10A, the FMR1 interacting protein CYFIP1, potassium channel genes KCNE1 and KCNE2, the Down Syndrome Critical Region 1 gene RCAN1, cell-recognition protein CHL1, the transcription factor SP4 and a histone deacetylase HDAC9 amongst others. Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge.

Data resources

1. What are copy number variants (CNVs)?

Copy number variations are spontaneous mutations in the genome that result in duplications or deletions of the genomic sequence. Duplications can produce extra copies of a gene, deletions can remove it altogether. CNVs are an interesting biological phenomenon because they are not inherited from ones parents. Rather, they are acquired de novo when certain sequences of genetic code fail to copy properly. Acquisition of CNVs is unpredictable, random, and spontaneous. Smaller variants are probably very common. Each one of us may have one or two (taken from G2COnline).

For full review see: 19748074

2. What is schizophrenia?

Schizophrenia is a psychiatric disorder characterized by abnormalities in the perception or expression of reality. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking with significant social or occupational dysfunction. See also Schizophrenia at Wikipedia.

3. What is the evidence CNVs are associated with schizophrenia?

Recent studies based on genome-wide study of CNVs have detected novel recurrent submicroscopic copy number changes, including recurrent deletions at a number of loci.

Available evidence is fully reviewed in: 19748074

4.How do we assay an indivdual's genome for CNVs?

Copy number variation can be asssayed by PCR and DNA array-based approaches. In the present study we utilised whole-genome tiling path array comparative genome hybridisation (array CGH). See e.g. methodological description by Catherine Shaffer.

5. What is the Lothian Birth Cohort (LBC)?

The Lothian Birth Cohort was obtained from the Scottish Mental Survey of 1947 (SMS1947; N = 70,805) examining individuals born in the year 1936 and residing in the Edinburgh area (Lothian) of Scotland. See 14717632 for full description.

6. What is CNVFinder?

CNVFinder is a programme designed to detect copy number variants (CNVs) in human population from large-insert clone DNA microarray data covering the entire human genome in tiling path resolution (WGTP platform). More information on the CNV Project is available on the Sanger website.

The algorithm is describes in 17122085

Supplementary Table 1. Technical confirmations of CNV calls.

Shown are the patient ID in which the CNV was detected, locus of the variation on the NCBI36 human genome assembly, whether predicted as a loss or gain by CNVFinder, result of confirmation by qPCR, Nimblegen result, and ISC coordinates of the variation.

Patient ID CNV Coordinates (NCBI36) CNVFinder qPCR Result Nimblegen Result ISC Coordinates (NCBI36)
3409 12:17761730-18154145 loss ok n/a n/a
5324 6:22212251-22607763 loss ok n/a n/a
1085 6:97469365-98475130 loss ok n/a n/a
ED1176 7:17795286-18873121 loss ok n/a n/a
4203 7:93658283-94064936 loss ok n/a n/a
3789 8:9670799-9988807 loss n/f ok n/a
3766 1:71346768-71893785 gain ok n/a n/a
3584 3:139094479-139416525 gain n/f n/f n/a
4179 9:137112070-137464520 gain ok ok n/a
5386 3:86998287-87223753 gain n/a ok n/a
5386 5:61438895-61723574 loss n/a ok n/a
3857 13:112568275-112939870 gain n/a n/a 13:112541419-112904310
3857 17:21109148-22170347 gain n/a n/a 17:21482690-22159778
621 2:24873682-25870859 loss n/a n/a 2:25485729-25865666
621 2:24873682-25870859 loss n/a n/a 2:24949186-25085976
621 2:24873682-25870859 loss n/a n/a 2:25191977-25321842
ED0903 21:34576662-34958227 gain n/a n/a 21:34644865-34827865
ED0903 3:6098521-6274110 loss n/a n/a 3:6052172-6244704
1085 6:97469365-98475130 loss n/a n/a 6:97426034-98410421
ED0908 11:31339431-31549584 gain n/a n/a 11:31312028-31554033
1295 5:25051484-25333181 gain n/a n/a 5:25121394-25405536
1295 7:88344724-88962788 loss n/a n/a 7:88292092-88731204
3141 n/f n/a n/a 5:17553826-17675250
3199 n/f n/a n/a 1:120784371-120956136
3409 12:17761730-18154145 loss n/a n/a 12:17776260-18038013
3443 n/f n/a n/a 19:6847380-7057724
3559 15:29725770-30375195 gain n/a n/a 15:29801634-30299513
3584 11:4012521-4399615 gain n/a n/a 11:4077830-4303386
3584 n/f n/a n/a 9:38979378-39305037
3652 15:30191187-30773871 loss n/a n/a 15:30318608-30664277
3703 n/f n/a n/a 7:21150024-21270602
ED0994 19:53868624-54100313 gain n/a n/a 19:53999273-54114243
ED0994 4:8933742-9123666 loss n/a n/a 4:9046959-9155615
3751 n/f n/a n/a 5:99347065-99474076
3815 6:1994541-2304998 gain n/a n/a 6:2001510-2293508
3815 n/f n/a n/a 9:74633392-75300129
3857 n/f n/a n/a 9:95716985-95909472
3945 3:189546565-189761158 loss n/a n/a 3:189564871-189682182
3945 4:28210870-28570510 loss n/a n/a 4:28415433-28541944
ED1024 2:127449511-127814482 gain n/a n/a 2:127182184-127688195
4100 14:74945402-75396561 gain n/a n/a 14:75046923-75379455
4111 18:1734176-1905685 loss n/a n/a 18:1715758-1828113
4179 21:30092743-30395434 loss n/a n/a 21:30189767-30289965
4179 n/f n/a n/a 9:135377617-135535293
ED1080 17:21191534-21340796 gain n/a n/a 17:21269272-21488331
ED1080 3:162804591-163099220 loss n/a n/a 3:162898816-163031692
4710 3:143326112-143612526 gain n/a n/a 3:143303643-143554513
4710 6:57644936-58888125 gain n/a n/a 6:57764260-58190911
4710 6:62001974-62186548 gain n/a n/a 6:61987979-62181322
4716 20:14561835-14926976 loss n/a n/a 20:14650902-14813485
4748 4:11678443-11990799 loss n/a n/a 4:11838410-11948682
5307 1:12596978-13667714 gain n/a n/a 1:12776194-12949762
5307 n/f n/a n/a 21:44730300-44890569
5446 2:97054767-97399962 loss n/a n/a 2:97166222-97295196
5446 7:75511690-76633111 gain n/a n/a 7:75780381-75933685
ED1176 16:18834998-19066807 gain n/a n/a 16:18811897-19027203
ED1176 7:17795286-18873121 loss n/a n/a 7:17674099-18634682
ED1176 8:13581607-13896999 loss n/a n/a 8:13684044-13829803
5562 19:59359391-59464094 gain n/a n/a 19:59432547-59539400
ED1213 8:6046013-6339195 gain n/a n/a 8:6115399-6290920
ED1213 n/f n/a n/a 21:13516106-14009921
6638 13:113166605-113658050 loss n/a n/a 13:113051168-113366491
6638 13:113166605-113658050 loss n/a n/a 13:113525792-113654850
6638 15:99707205-100036184 gain n/a n/a 15:99764132-99956872
6667 20:9592231-9923810 gain n/a n/a 20:9685413-9834501
6667 5:17286078-17757290 loss n/a n/a 5:17369993-17568802
7132 n/f n/a n/a 4:93752699-93865582
7183 15:28080236-30412040 gain n/a n/a 15:28608929-30599822
7294 10:80945468-81607519 gain n/a n/a 10:81475459-81588070
7294 n/f n/a n/a 3:50339490-50452892
7294 n/f n/a n/a 11:63498551-63605997
5758 6:165840859-166673790 gain n/a n/a 6:165893867-166666551
5758 n/f n/a n/a 11:66646290-67038667
5758 n/f n/a n/a 9:135377617-135537967
5758 n/f n/a n/a 11:65426675-65585941
5758 n/f n/a n/a 9:137495692-137862491
5758 n/f n/a n/a 1:151959187-152132074
297 n/f n/a n/a 5:104437565-104653030
297 n/f n/a n/a 7:125354682-125517636
297 n/f n/a n/a 1:195349228-195455619
297 n/f n/a n/a 2:194527820-194654919
297 n/f n/a n/a 6:102421721-102577471
297 n/f n/a n/a 7:118870202-119151500
297 n/f n/a n/a 13:86534961-86680013
297 n/f n/a n/a 7:108960973-109127453
297 n/f n/a n/a 21:19222152-19326789
297 n/f n/a n/a 8:114240032-114397512
297 n/f n/a n/a 2:70019722-70390224
297 n/f n/a n/a 21:19996804-20119037
297 n/f n/a n/a 7:44379457-44481778
3766 1:68325266-68897278 gain n/a n/a 1:68334011-68755246
3766 1:71346768-71893785 gain n/a n/a 1:71379226-71687039
3766 21:13556403-13942143 loss n/a n/a 21:13610220-13985450
3766 n/f n/a n/a 19:18037250-18203869
3766 n/f n/a n/a 19:846638-1231660
3766 n/f n/a n/a 19:16292361-16581261
3766 n/f n/a n/a 11:62107734-62354294
3766 n/f n/a n/a 11:72061419-72225335
3766 n/f n/a n/a 13:17924949-18160113
3766 n/f n/a n/a 19:13761432-14159634
3766 n/f n/a n/a 20:33710437-33886157
3766 n/f n/a n/a 9:136571119-136733304

Supplementary Table 2. Genic case-specific ISC CNVs confirmed by CNVFinder.

Shown are HGNC-approved gene symbols and IDs, locus of the variation on the NCBI36 human genome assembly, detection in the various patient and control cohorts, and whether the variation in an insertion or deletion.

HGNC Symbol HGNC ID Locus (NCBI36) SCZ91 LBC92 ISC Cases ISC Controls Indel
FAM87B HGNC:32236 1:742614-745077 1 0 1 0 ins
FAHD2B HGNC:25318 2:97113051-97124309 1 0 1 0 del
BIN1 HGNC:1052 2:127522073-127581334 1 0 1 0 ins
CYP27C1 HGNC:33480 2:127657888-127694124 1 0 1 0 ins
ERCC3 HGNC:3435 2:127731336-127768222 1 0 1 0 ins
ZNF804A HGNC:21711 2:185171932-185512457 1 0 1 0 ins
GULP1 HGNC:18649 2:188864641-189168898 1 0 1 0 ins
CHL1 HGNC:1939 3:213650-426098 5 0 1 0 del
EHHADH HGNC:3247 3:186391108-186454531 1 0 1 0 ins
PDS5A HGNC:29088 4:39500879-39655971 3 0 2 0 ins
TRIML1 HGNC:26698 4:189297592-189305643 1 0 2 0 del
GMDS HGNC:4369 6:1569040-2190845 1 0 4 0 ins
RREB1 HGNC:10449 6:7052829-7197212 1 0 1 0 ins
NUDT3 HGNC:8050 6:34363982-34468419 1 0 1 0 ins
RPS10 HGNC:10383 6:34493209-34501814 1 0 1 0 ins
RPS10P11 HGNC:36775 6:34493209-34501814 1 0 1 0 ins
RPS10P13 HGNC:36374 6:34493209-34501814 1 0 1 0 ins
RPS10P22 HGNC:35814 6:34493209-34501814 1 0 1 0 ins
RPS10P4 HGNC:31364 6:34493209-34501814 1 0 1 0 ins
TBP HGNC:11588 6:170705384-170723869 1 0 1 0 ins
PDCD2 HGNC:8762 6:170728375-170735673 1 0 1 0 ins
HDAC9 HGNC:14065 7:18501894-19003518 1 0 1 0 del
SP4 HGNC:11209 7:21434214-21520674 1 0 2 0 del
BET1 HGNC:14562 7:93430021-93471626 1 0 1 0 del
COL1A2 HGNC:2198 7:93861809-93898480 1 0 1 0 del
CASD1 HGNC:16014 7:93977120-94024215 1 0 1 0 del
TNKS HGNC:11941 8:9450855-9677266 1 0 1 0 del
MSRA HGNC:7377 8:9949189-10323803 1 0 1 0 del
DMRT1 HGNC:2934 9:831690-959088 1 0 1 0 ins
KCNT1 HGNC:18865 9:137733859-137826386 1 0 1 0 ins
NACC2 HGNC:23846 9:138038204-138126952 3 0 1 0 ins
MUC2 HGNC:7512 11:1064875-1088828 1 0 1 0 ins
MUC5AC HGNC:7515 11:1152663-1178504 1 0 1 0 ins
MUC5B HGNC:7516 11:1200872-1239982 1 0 1 0 ins
OR52K2 HGNC:15223 11:4427146-4452507 2 0 1 0 del
OR52K3P HGNC:15224 11:4453046-4453699 2 0 1 0 del
OR52K1 HGNC:15222 11:4466707-4467651 2 0 1 0 del
MPHOSPH8 HGNC:29810 13:19105880-19144638 1 0 1 0 ins
GPC6 HGNC:4454 13:92677711-93853948 1 0 1 0 del
TTLL5 HGNC:19963 14:75197374-75491174 1 0 1 0 ins
MKRN3 HGNC:7114 15:21361547-21364653 2 0 1 0 del
HISPPD2A HGNC:29023 15:41612952-41764218 1 0 1 0 ins
CATSPER2 HGNC:18810 15:41707993-41747608 1 0 1 0 ins
CKMT1A HGNC:31736 15:41772376-41778712 1 0 1 0 ins
PDIA3 HGNC:4606 15:41825882-41852093 1 0 1 0 ins
ELL3 HGNC:23113 15:41852107-41857033 1 0 1 0 ins
SERF2 HGNC:10757 15:41856590-41881572 1 0 1 0 ins
SERINC4 HGNC:32237 15:41873652-41888067 1 0 1 0 ins
MFAP1 HGNC:7032 15:41884025-41904243 1 0 1 0 ins
ZNF205 HGNC:12996 16:3102564-3110517 1 0 1 0 ins
ZNF213 HGNC:13005 16:3125140-3132805 1 0 1 0 ins
OR1F1 HGNC:8194 16:3194248-3195189 1 0 1 0 ins
ZNF200 HGNC:12993 16:3212326-3225412 1 0 1 0 ins
ATP2C2 HGNC:29103 16:82959634-83055293 1 0 2 0 ins
COTL1 HGNC:18304 16:83156738-83209203 1 0 1 0 ins
CA5A HGNC:1377 16:86479126-86527613 1 0 2 0 ins
BANP HGNC:13450 16:86542539-86668425 1 0 2 0 ins
PITPNA HGNC:9001 17:1368037-1412835 1 0 1 0 del
WSCD1 HGNC:29060 17:5914658-5968469 1 0 2 0 del
UNC45B HGNC:14304 17:30498949-30540477 1 0 1 0 ins
AMAC1 HGNC:26848 17:30543652-30545560 1 0 1 0 ins
SLFN5 HGNC:28286 17:30594199-30618852 1 0 1 0 ins
ANKRD12 HGNC:29135 18:9126758-9275206 1 0 1 0 ins
CCDC102B HGNC:26295 18:64616297-64873406 1 0 1 0 ins
ELAVL1 HGNC:3312 19:7929458-8415925 1 0 1 0 ins
LASS4 HGNC:23747 19:8180257-8233302 1 0 1 0 ins
CD320 HGNC:16692 19:8273011-8279239 1 0 1 0 ins
NDUFA7 HGNC:7691 19:8282234-8292280 1 0 1 0 ins
KANK3 HGNC:24796 19:8293469-8314146 1 0 1 0 ins
ANGPTL4 HGNC:16039 19:8335011-8345257 1 0 1 0 ins
RAB11B HGNC:9761 19:8361301-8375318 1 0 1 0 ins
FPR2 HGNC:3827 19:56955995-56965572 1 0 1 0 ins

References

  • The role of DNA copy number variation in schizophrenia.

    Tam GW, Redon R, Carter NP and Grant SG

    Biological psychiatry 2009;66;11;1005-12

  • Accurate and reliable high-throughput detection of copy number variation in the human genome.

    Fiegler H, Redon R, Andrews D, Scott C, Andrews R, Carder C, Clark R, Dovey O, Ellis P, Feuk L, French L, Hunt P, Kalaitzopoulos D, Larkin J, Montgomery L, Perry GH, Plumb BW, Porter K, Rigby RE, Rigler D, Valsesia A, Langford C, Humphray SJ, Scherer SW, Lee C, Hurles ME and Carter NP

    Genome research 2006;16;12;1566-74

  • The impact of childhood intelligence on later life: following up the Scottish mental surveys of 1932 and 1947.

    Deary IJ, Whiteman MC, Starr JM, Whalley LJ and Fox HC

    Journal of personality and social psychology 2004;86;1;130-47

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.