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Genomic structural variants are linked with intellectual disability

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Abstract

Mutations in more than 500 genes have been associated with intellectual disability (ID) and related disorders of cognitive function, such as autism and schizophrenia. Here we aimed to unravel the molecular epidemiology of non-specific ID in a genetic isolate using a combination of population and molecular genetic approaches. A large multigenerational pedigree was ascertained within a Dagestan Genetic Heritage research program in a genetic isolate of indigenous ethnics. Clinical characteristics of the affected members were based on combining diagnoses from regional psychiatric hospitals with our own clinical assessment, using a Russian translation of the structured psychiatric interviews, the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies, based on DSM-IV criteria. Weber/CHLC 9.0 STRs set was used for multipoint parametric linkage analyses (Simwalk2.91). Next, we checked CNVs and LOH (based on Affymetrix SNP 5.0 data) in the linked with ID genomic regions with the aim to identify candidate genes associated with mutations in linked regions. The number of statistically significant (p ≤ 0.05) suggestive linkage peaks with 1.3 < LOD < 3.0 we detected in a total of 10 genomic regions: 1q41, 2p25.3-p24.2, 3p13-p12.1, 4q13.3, 10p11, 11q23, 12q24.22-q24.31, 17q24.2-q25.1, 21q22.13 and 22q12.3-q13.1. Three significant linkage signals with LOD >3 were obtained at 2p25.3-p24.2 under the dominant model, with a peak at 21 cM flanked by loci D2S2976 and D2S2952; at 12q24.22-q24.31 under the recessive model, with a peak at −120 cM flanked by marker D12S2070 and D12S395 and at 22q12.3 under the dominant model, with a peak at 32 cM flanked by marker D22S683 and D22S445. After a set of genes had been designated as possible candidates in these specific chromosomal regions,we conducted an exploratory search for LOH and CNV based on microarray data to detect structural genomic variants within five ID-linked regions with LOD scores between 2.0 and 3.9. In these selected regions we obtained 173 ROH segments and 98 CN segments. Further analysis of region 2p25.3-p24.2 revealed deletions within genes encoding MYTL, SNTG2 and TPO among five of 21 affected cases at 2p25.3-p24.2. In the ID-linked region at 12q24.22-12q24.31 19 out of 21 ID cases carried segmental CNV and 20 of 21 them displayed ROH segments with mean size lengths for ID cases 2512 kb (500–6,472 kb) and for healthy control 682 kb (531–986 kb), including the genes MED13L, HRK, FBXW8, TESC, CDK2AP1 and SBNO1. Seven of 21 affected pedigree members displayed segmental deletions at 22q12.3 that includes the gene LARGE. Eight affected pedigree members carried ROH segments and 6 CN segments at 10p11.23-p11.21 containing the genes ZEB1, c10orf68 and EPC1. Our linkage and structural genomic variation analyses in a remote highland genetic isolate with aggregation of ID demonstrated that even highly isolated single kindred ID has oligo/polygenic pathogenesis. The results obtained implicate 10 genomic regions linked with ID that contain some of previously reported candidate genes, including HRK, FBXW8, TESC, CDK2AP1 and SBNO1 at 12q24 that were shown in recent studies as associated with brain measures derived from MRI scans.

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References

  • Alkuraya FS (2013) Impact of new genomic tools on the practice of clinical genetics in consanguineous populations: the Saudi experience. Clin Genet 84:203–208

    Article  CAS  PubMed  Google Scholar 

  • Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J (1998) Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry 55:663–664

    CAS  PubMed  Google Scholar 

  • Bis JC, DeCarli C, Smith AV, van der Lijn V, Crivello F, Fornage M et al (2012) Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nat Genet 44:545–551

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brouwer RM, Mandl RC, Schnack HG, van Soelen IL, van Baal GC, Peper JS et al (2012) White matter development in early puberty: a longitudinal volumetric and diffusion tensor imaging twin study. PLoS One 7:e32316

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bulayeva KB, Leal S, Pavlova TA, Kurbanov RM, Coover S, Bulayev OA, Byerley W (2000) The ascertainment of schizophrenia pedigrees in Dagestan genetic isolates. Psychiatr Genet 10(2):67–72

    Article  CAS  PubMed  Google Scholar 

  • Bulayeva KB, Pavlova TA, Kurbanov RM, Bulayev OA (2002) Mapping genes of complex diseases in genetic isolates of Dagestan. Genetika 38(11):1539–1548

    Google Scholar 

  • Bulayeva KB, Pavlova TA, Kurbanov RM, Leal S, Bulayev OA (2003) Genetic and epidemiological studies in Daghestan highland isolates. Genetika 39(12):333–341

    CAS  Google Scholar 

  • Bulayeva KB, Leal SM, Pavlova TA, Kurbanov RM, Glatt SJ, Bulayev OA et al (2005) Mapping genes of complex psychiatric diseases in Daghestan genetic isolates. Am J Med Genet B Neuropsychiatr Genet 132B(1):76–84

    Article  PubMed  Google Scholar 

  • Bulayeva KB, Glatt SJ, Bulayev OA, Pavlova TA, Tsuang MT (2007) Genome-wide linkage scan of schizophrenia: a cross-isolate study. Genomics 89:167–177

    Article  CAS  PubMed  Google Scholar 

  • Bulayeva KB, Lencz T, Glatt S, Takumi T, Gurgenova FR, Bulayev OA (2011) Genome-wide linkage scan of major depressive disorder in two Dagestan genetic isolates. Cent Eur J Med 6:616–624

    Google Scholar 

  • Burgess N, Maguire EA, O’Keefe J (2002) The human hippocampus and spatial and episodic memory. Neuron 35:625–641

    Article  CAS  PubMed  Google Scholar 

  • Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME (1992) A functional anatomical study of unipolar depression. J Neurosci 12:3628–3641

    CAS  PubMed  Google Scholar 

  • Freitag CM, Luders E, Hulst HE, Narr KL, Thompson PM, Toga AW, Krick C, Konrad C (2009) Total brain volume and corpus callosum size in medication-naive adolescents and young adults with autism spectrum disorder. Biol Psychiatry 66:316–319

    Article  PubMed Central  PubMed  Google Scholar 

  • Goldberg TE, Torrey EF, Berman KF, Weinberger DR (1994) Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia. Psychiatry Res 55:51–61

    Article  CAS  PubMed  Google Scholar 

  • Hirayasu Y, Shenton ME, Salisbury DF, Dickey CC, Fischer IA, Mazzoni P et al (1998) Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry 155:1384–1391

    Article  CAS  PubMed  Google Scholar 

  • Ikram MA, Fornage M, Smith AV, Seshadri S, Schmidt R et al (2012) Common variants at 6q22 and 17q21 are associated with intracranial volume. Nat Genet 44:539–544

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jack CR Jr, Barkhof F, Bernstein MA, Cantillon M, Cole PE, Decarli C, Dubois B, Duchesne S, Fox NC, Frisoni GB, Hampel H, Hill DL, Johnson K, Mangin JF, Scheltens P, Schwarz AJ, Sperling R, Suhy J, Thompson PM, Weiner M, Foster NL (2011) Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer’s disease. Alzheimers Dement 7(4):474–485.e4

    Article  PubMed Central  PubMed  Google Scholar 

  • Kaufman L, Ayub M, Vincent JB (2010) The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord 2(4):182–209

    Article  PubMed Central  PubMed  Google Scholar 

  • Kremen WS, Jacobson KC (2010) Introduction to the special issue, pathways between genes, brain, and behavior. Behav Genet 40:111–113

    Article  PubMed Central  PubMed  Google Scholar 

  • Lee Y, Mattai A, Long R, Rapoport JL, Gogtay N, Addington AM (2012) Microduplications disrupting the MYT1L gene (2p25.3) are associated with schizophrenia. Psychiatr Genet 22:206–209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lencz T, Lambert C, DeRosse P, Burdick KE, Morgan TV, Kane JM et al (2007) Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. PNAS 104:19942–19947

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Röser C, Nguyen TT, Craig DW, Romanos J, Heine M, Meyer J, Freitag C, Warnke A, Romanos M, Schäfer H, Walitza S, Reif A, Stephan DA, Jacob C (2008) Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 115:1573–1585

    Article  CAS  PubMed  Google Scholar 

  • Levay K, Slepak VZ (2007) Tescalcin is an essential factor in megakaryocytic differentiation associated with Ets family gene expression. J Clin Invest 117:2672–2683

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Levay K, Slepak VZ (2010) Up- or downregulation of tescalcin in HL-60 cells is associated with their differentiation to either granulocytic or macrophage-like lineage. Exp Cell Res 316:1254–1262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li W, Wang X, Zhao J, Lin J, Song XQ, Yang Y et al (2012) Association study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population. Genes Brain Behav 11:87–93

    Article  PubMed  Google Scholar 

  • Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS, Fritht CD (2000) Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci USA 97:4398–4403

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mayberg HS (1993) Neuroimaging studies of depression in neurologic disease. In: Starkstein SE, Robinson RG (eds) Depression in neurological disease. Johns Hopkins University Press, Baltimore, pp 186–216

    Google Scholar 

  • Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS et al (2011) Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 7367:57–63

    Article  Google Scholar 

  • Nestor PG, Shenton ME, McCarley RW, Haimson J, Smith RS, O’Donnell B et al (1993) Neuropsychological correlates of MRI temporal lobe abnormalities in schizophrenia. Am J Psychiatry 150:1849–1855

    Article  CAS  PubMed  Google Scholar 

  • Nurnberger J, Blehar M, Kaufman C, York-Cooler C, Simpson S, Harkavy-Friedman J et al (1994) Diagnostic interview for genetic studies: rationale, unique features and training. Arch Gen Psychiatry 51:849–862

    Article  PubMed  Google Scholar 

  • Pahari DR, Gu YJ, van Oeveren W, El-Essawi A, Harringer W, Brouwer RM (2013) Effect of minimized perfusion circuit on brain injury markers carnosinase and brain-type fatty binding protein in coronary artery bypass grafting patients. Artif Org 37:128–135

    Article  CAS  Google Scholar 

  • Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Pol H, Hilleke E (2007) Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Mapp 28:464–473

    Article  PubMed  Google Scholar 

  • Roeleveld N, Zielhuis GA, Gabreëls F (1997) The prevalence of mental retardation: a critical review of recent literature. Dev Med Child Neurol 39(2):125–132

    Article  CAS  PubMed  Google Scholar 

  • Simic G, Kostovic I, Winblad B, Bogdanovic N (1997) Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. J Comp Neurol 379:482–494

    Article  CAS  PubMed  Google Scholar 

  • Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA (2011) Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476:458–461

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker sharing statistics. Am J Hum Genet 58:1323–1337

    PubMed Central  CAS  PubMed  Google Scholar 

  • Stein JL, Hibar DP, Madsen SK et al (2011) Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N = 1198) using genome-wide search. Mol Psychiatry 16:927–937. doi:10.1038/mp.2011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM et al (2012) Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet 44:552–561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stevens SJ, van Ravenswaaij-Arts CM, Janssen JW, Klein Wassink-Ruiter JS, van Essen AJ, Dijkhuizen T et al (2011) MYT1L is a candidate gene for intellectual disability in patients with 2p25.3 (2pter) deletions. Am J Med Genet A 155A:2739–2745

    Article  PubMed  Google Scholar 

  • Taal HR, St Pourcain B, Thiering E, Das S, Mook-Kanamori DO, Warrington NM et al (2012) Common variants at 12q15 and 12q24 are associated with infant head circumference. Nat Genet 44:532–538

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Takano A, Zochi R, Hibi M, Terashima T, Katsuyama Y (2011) Function of strawberry notch family genes in the zebrafish brain development. Kobe J Med Sci 56:E220–E230

    PubMed  Google Scholar 

  • Thompson PM, Stein JL, Medland SE, Hibar DP, Vasquez AA, Renteria ME, Toro R et al (2014) The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging Behav 8(1):153–182

    PubMed Central  PubMed  Google Scholar 

  • Velakoulis D, Pantelis C, McGorry PD, Dudgeon P, Brewer W, Cook M et al (1999) Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry 56:133–141

    Article  CAS  PubMed  Google Scholar 

  • Videbech P, Ravnkilde B (2004) Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 161:1957–1966

    Article  PubMed  Google Scholar 

  • Weber JL, Wang Z, Hansen K, Stephenson M, Kappel C, Salzman Sh, Wilkie PJ, Keats B, Dracopoli NC, Brandriff BF, Olsenet AS (1993) Evidence for human meiotic recombination: interference obtained through construction of a short tandem repeat-polymorphism linkage map of chromosome 19. Am J Hum Genet 53:1079–1095

    PubMed Central  CAS  PubMed  Google Scholar 

  • Weinberger DR (1999) Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry 45:395–402

    Article  CAS  PubMed  Google Scholar 

  • Yeargin-Allsopp M, Murphy CC, Cordero JF, Decouflé P, Hollowell JG (1997) Reported biomedical causes and associated medical conditions for mental retardation among 10-year-old children, metropolitan Atlanta, 1985 to 1987. Dev Med Child Neurol 39(3):142–149

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by research grants from the RFBR and ‘Dynamics of Gene Pools’ of RAS Council.

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Correspondence to Kazima Bulayeva.

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Bulayeva, K., Lesch, KP., Bulayev, O. et al. Genomic structural variants are linked with intellectual disability. J Neural Transm 122, 1289–1301 (2015). https://doi.org/10.1007/s00702-015-1366-8

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