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Schizophrenia 15(SCZD15)

MedGen UID:
462730
Concept ID:
C3151380
Mental or Behavioral Dysfunction
Synonyms: SCHIZOPHRENIA SUSCEPTIBILITY LOCUS, CHROMOSOME 22q13-RELATED; SCZD15
 
Gene (location): SHANK3 (22q13.33)
 
Monarch Initiative: MONDO:0013498
OMIM®: 613950

Definition

A schizophrenia that has material basis in a mutation of SHANK3 on chromosome 22q13.33. [from MONDO]

Clinical features

From HPO
Schizophrenia
MedGen UID:
48574
Concept ID:
C0036341
Mental or Behavioral Dysfunction
Schizophrenia is highly heritable, as shown by family, twin, and adoption studies. For example, for identical twins, if one twin develops schizophrenia, the other twin has about a 50% chance of also developing the disease. The risk of the general population developing the schizophrenia is about 0.3-0.7% worldwide. The search for “schizophrenia genes” has been elusive. Initial linkage studies looked at parts of the genome associated with schizophrenia, and many candidate genes were identified, including APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53, and TPH1. However, some of these have later been questioned. Microdeletions and microduplications have been found to be three times more common in individuals with schizophrenia, compared to controls. Because these deletions and duplications are in genes that are overexpressed in pathways related to brain development, it is possible that the inheritance of multiple rare variants may contribute to the development of schizophrenia. Several genetic disorders feature schizophrenia as a clinical feature. The 22q11.2 Deletion Syndrome comprises many different syndromes, of which one of the most serious is DiGeorge syndrome. Children born with DiGeorge syndrome typically have heart defects, cleft palate, learning difficulties, and immune deficiency. Schizophrenia is a late manifestation, affecting around 30% of individuals. Microdeletions and duplications in chromosome 1, 2, 3, 7, 15 and 16 have also been associated with schizophrenia. In 2014, a genome-wide association study looked at the genomes of over 35,000 patients and 110,00 controls. The study identified 108 SNPs that were associated with schizophrenia, 83 of which had not been previously reported. As expected, many of these loci occurred in genes that are expressed in the brain. For example, the SNPs included a gene that encodes the dopamine D2 receptor, DRD2 (the target of antipsychotic drugs), and many genes involved in glutamine neurotransmitter pathways and synaptic plasticity (e.g., GRM3, GRIN2A, SRR, GRIA1). More surprisingly, however, associations were also enriched among genes expressed in tissues with important immune functions. In 2016, a study based on nearly 65,000 people investigated the association between schizophrenia and variation in the Major Histocompatibility Complex (MHC) locus—a region on chromosome 6 that is important for immune function. The study focused on the C4 gene (complement component 4) that exists as two distinct genes: C4A and C4B, which encode particularly structurally diverse alleles. The study found that the alleles which promoted greater expression of C4A in the brain were associated with a greater risk of schizophrenia. By using mice models, the study showed that C4 is involved in the elimination of synapses during brain maturation. In humans, “synaptic pruning” is most active during late adolescence, which coincides with the typical onset of symptoms of schizophrenia. It is therefore possible that the inheritance of specific C4A alleles could lead to “run away” synaptic pruning, increasing the risk of schizophrenia. Further research may even determine C4 as a potential therapeutic target.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.

Professional guidelines

PubMed

Stip E, Cherbal A, Luck D, Zhornitsky S, Bentaleb LA, Lungu O
Psychopharmacology (Berl) 2017 Apr;234(7):1045-1058. Epub 2017 Feb 17 doi: 10.1007/s00213-017-4533-9. PMID: 28210783
Koutsouleris N, Meisenzahl EM, Borgwardt S, Riecher-Rössler A, Frodl T, Kambeitz J, Köhler Y, Falkai P, Möller HJ, Reiser M, Davatzikos C
Brain 2015 Jul;138(Pt 7):2059-73. Epub 2015 May 1 doi: 10.1093/brain/awv111. PMID: 25935725Free PMC Article
Haier RJ, Rieder RO, Khouri PJ, Buchsbaum MS
Arch Gen Psychiatry 1979 May;36(5):528-34. doi: 10.1001/archpsyc.1979.01780050038003. PMID: 435013

Recent clinical studies

Etiology

Owen MJ, Legge SE, Rees E, Walters JTR, O'Donovan MC
Mol Psychiatry 2023 Sep;28(9):3638-3647. Epub 2023 Oct 18 doi: 10.1038/s41380-023-02293-8. PMID: 37853064Free PMC Article
Hagi K, Nosaka T, Dickinson D, Lindenmayer JP, Lee J, Friedman J, Boyer L, Han M, Abdul-Rashid NA, Correll CU
JAMA Psychiatry 2021 May 1;78(5):510-518. doi: 10.1001/jamapsychiatry.2021.0015. PMID: 33656533Free PMC Article
McCutcheon RA, Reis Marques T, Howes OD
JAMA Psychiatry 2020 Feb 1;77(2):201-210. doi: 10.1001/jamapsychiatry.2019.3360. PMID: 31664453
Shimada T, Ito S, Makabe A, Yamanushi A, Takenaka A, Kobayashi M
Psychiatry Res 2019 Dec;282:112638. Epub 2019 Nov 1 doi: 10.1016/j.psychres.2019.112638. PMID: 31685285
McGrath J, Saha S, Chant D, Welham J
Epidemiol Rev 2008;30:67-76. Epub 2008 May 14 doi: 10.1093/epirev/mxn001. PMID: 18480098

Diagnosis

Owen MJ, Legge SE, Rees E, Walters JTR, O'Donovan MC
Mol Psychiatry 2023 Sep;28(9):3638-3647. Epub 2023 Oct 18 doi: 10.1038/s41380-023-02293-8. PMID: 37853064Free PMC Article
Grant RK, Brindle WM, Donnelly MC, McConville PM, Stroud TG, Bandieri L, Plevris JN
World J Gastroenterol 2022 Oct 14;28(38):5515-5529. doi: 10.3748/wjg.v28.i38.5515. PMID: 36304087Free PMC Article
Gebreegziabhere Y, Habatmu K, Mihretu A, Cella M, Alem A
Eur Arch Psychiatry Clin Neurosci 2022 Oct;272(7):1139-1155. Epub 2022 May 28 doi: 10.1007/s00406-022-01416-6. PMID: 35633394Free PMC Article
McCutcheon RA, Reis Marques T, Howes OD
JAMA Psychiatry 2020 Feb 1;77(2):201-210. doi: 10.1001/jamapsychiatry.2019.3360. PMID: 31664453
Siris SG
J Psychopharmacol 2001 Jun;15(2):127-35. doi: 10.1177/026988110101500209. PMID: 11448086

Therapy

McCutcheon RA, Reis Marques T, Howes OD
JAMA Psychiatry 2020 Feb 1;77(2):201-210. doi: 10.1001/jamapsychiatry.2019.3360. PMID: 31664453
Shimada T, Ito S, Makabe A, Yamanushi A, Takenaka A, Kobayashi M
Psychiatry Res 2019 Dec;282:112638. Epub 2019 Nov 1 doi: 10.1016/j.psychres.2019.112638. PMID: 31685285
Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Bäckers L, Rothe P, Cipriani A, Davis J, Salanti G, Leucht S
Lancet 2019 Sep 14;394(10202):939-951. Epub 2019 Jul 11 doi: 10.1016/S0140-6736(19)31135-3. PMID: 31303314Free PMC Article
Geretsegger M, Mössler KA, Bieleninik Ł, Chen XJ, Heldal TO, Gold C
Cochrane Database Syst Rev 2017 May 29;5(5):CD004025. doi: 10.1002/14651858.CD004025.pub4. PMID: 28553702Free PMC Article
Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM
Lancet 2013 Sep 14;382(9896):951-62. Epub 2013 Jun 27 doi: 10.1016/S0140-6736(13)60733-3. PMID: 23810019

Prognosis

Hansen HG, Starzer M, Nilsson SF, Hjorthøj C, Albert N, Nordentoft M
JAMA Psychiatry 2023 Apr 1;80(4):371-379. doi: 10.1001/jamapsychiatry.2022.5164. PMID: 36811902Free PMC Article
Koutsouleris N, Dwyer DB, Degenhardt F, Maj C, Urquijo-Castro MF, Sanfelici R, Popovic D, Oeztuerk O, Haas SS, Weiske J, Ruef A, Kambeitz-Ilankovic L, Antonucci LA, Neufang S, Schmidt-Kraepelin C, Ruhrmann S, Penzel N, Kambeitz J, Haidl TK, Rosen M, Chisholm K, Riecher-Rössler A, Egloff L, Schmidt A, Andreou C, Hietala J, Schirmer T, Romer G, Walger P, Franscini M, Traber-Walker N, Schimmelmann BG, Flückiger R, Michel C, Rössler W, Borisov O, Krawitz PM, Heekeren K, Buechler R, Pantelis C, Falkai P, Salokangas RKR, Lencer R, Bertolino A, Borgwardt S, Noethen M, Brambilla P, Wood SJ, Upthegrove R, Schultze-Lutter F, Theodoridou A, Meisenzahl E; PRONIA Consortium
JAMA Psychiatry 2021 Feb 1;78(2):195-209. doi: 10.1001/jamapsychiatry.2020.3604. PMID: 33263726Free PMC Article
Hjorthøj C, Stürup AE, McGrath JJ, Nordentoft M
Lancet Psychiatry 2017 Apr;4(4):295-301. Epub 2017 Feb 22 doi: 10.1016/S2215-0366(17)30078-0. PMID: 28237639
McGrath J, Saha S, Chant D, Welham J
Epidemiol Rev 2008;30:67-76. Epub 2008 May 14 doi: 10.1093/epirev/mxn001. PMID: 18480098
Auquier P, Lançon C, Rouillon F, Lader M, Holmes C
Pharmacoepidemiol Drug Saf 2006 Dec;15(12):873-9. doi: 10.1002/pds.1325. PMID: 17058327

Clinical prediction guides

Owen MJ, Legge SE, Rees E, Walters JTR, O'Donovan MC
Mol Psychiatry 2023 Sep;28(9):3638-3647. Epub 2023 Oct 18 doi: 10.1038/s41380-023-02293-8. PMID: 37853064Free PMC Article
Pillinger T, Osimo EF, de Marvao A, Shah M, Francis C, Huang J, D'Ambrosio E, Firth J, Nour MM, McCutcheon RA, Pardiñas AF, Matthews PM, O'Regan DP, Howes OD
Lancet Psychiatry 2023 Feb;10(2):98-107. Epub 2023 Jan 8 doi: 10.1016/S2215-0366(22)00403-5. PMID: 36632818
Citrome L, Preskorn SH, Lauriello J, Krystal JH, Kakar R, Finman J, De Vivo M, Yocca FD, Risinger R, Rajachandran L
J Clin Psychiatry 2022 Oct 3;83(6) doi: 10.4088/JCP.22m14447. PMID: 36198061
Leucht S, Bauer S, Siafis S, Hamza T, Wu H, Schneider-Thoma J, Salanti G, Davis JM
JAMA Psychiatry 2021 Nov 1;78(11):1238-1248. doi: 10.1001/jamapsychiatry.2021.2130. PMID: 34406325Free PMC Article
McCutcheon RA, Reis Marques T, Howes OD
JAMA Psychiatry 2020 Feb 1;77(2):201-210. doi: 10.1001/jamapsychiatry.2019.3360. PMID: 31664453

Recent systematic reviews

Bilbao A, Spanagel R
BMC Med 2022 Aug 19;20(1):259. doi: 10.1186/s12916-022-02459-1. PMID: 35982439Free PMC Article
McGuinness AJ, Davis JA, Dawson SL, Loughman A, Collier F, O'Hely M, Simpson CA, Green J, Marx W, Hair C, Guest G, Mohebbi M, Berk M, Stupart D, Watters D, Jacka FN
Mol Psychiatry 2022 Apr;27(4):1920-1935. Epub 2022 Feb 22 doi: 10.1038/s41380-022-01456-3. PMID: 35194166Free PMC Article
GBD 2019 Mental Disorders Collaborators
Lancet Psychiatry 2022 Feb;9(2):137-150. Epub 2022 Jan 10 doi: 10.1016/S2215-0366(21)00395-3. PMID: 35026139Free PMC Article
Jutla A, Foss-Feig J, Veenstra-VanderWeele J
Autism Res 2022 Mar;15(3):384-412. Epub 2021 Dec 29 doi: 10.1002/aur.2659. PMID: 34967130Free PMC Article
Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Bäckers L, Rothe P, Cipriani A, Davis J, Salanti G, Leucht S
Lancet 2019 Sep 14;394(10202):939-951. Epub 2019 Jul 11 doi: 10.1016/S0140-6736(19)31135-3. PMID: 31303314Free PMC Article

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