Abstract
There is a pressing need for novel pharmaceutical interventions for the major neuropsychiatric diseases schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), and autism spectrum disorder (ASD). The heritable component of these disorders provides an avenue for understanding disease mechanism leading to novel pharmaceutical interventions. Progress toward this understanding is described. Variations in the genome include single nucleotide polymorphisms (SNPs) generally but not always of small effect size. Only a small subset of SNPs are within protein coding sequences. Structural variants (SVs) including copy number repeats (CNVs) can have larger influence on phenotype. These genetic variations are queried for influence on diseases using genome-wide association studies (GWASs) to reveal a largely polygenic influence on disease. This consists of multiple small contributions from common polymorphisms. Mutations with large effect size, for example from protein coding changes or chromosomal structural variations, often include de novo mutations. These also influence neuropsychiatric disease. Importantly, the genetic findings cross current diagnostic boundaries. The genomic studies seek improved mechanistic understanding leading to improved diagnostic and clinical practice and importantly provision of a basis for discovery of novel pharmaceuticals. Efforts toward these goals are discussed.
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References
Ban TA (2007) Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat 3(4):495–500
Barondes S (1993) Molecules and mental illness. Scientific American Library HPHLP, New York
Breen G et al (2016) Translating genome-wide association findings into new therapeutics for psychiatry. Nat Neurosci 19(11):1392–1396. https://doi.org/10.1038/nn.4411
Brennand K et al (2011) Modeling schizophrenia using hiPSC neurons. Nature 473(7346):221–225. https://doi.org/10.1038/nature09915
Brunton L, Hilal-Dandan R, Knollmann B (2018) Goodman & Gilman’s: the pharmacological basis of therapeutics, 13e, 13th edn. McGraw Hill, New York
Cade J (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust 2(10):349–351
Charlesworth B (2012) The role of background selection in shaping patterns of molecular evolution and variation: evidence from variability on the Drosophila X chromosome. Genetics 191(1):233–246. https://doi.org/10.1534/genetics.111.138073
Consortium Cross-Disorder Phenotype Group of the Psychiatric GWAS (2009) Dissecting the phenotype in genome-wide association studies of psychiatric illness. Br J Psychiatry 195(2):97–99
Corvin A, Craddock N, Sullivan P (2010) Genome-wide association studies: a primer. Psychol Med 40(7):1063–1077. https://doi.org/10.1017/S0033291709991723
Craddock N, Owen MJ (2010) The Kraepelinian dichotomy – going, going... But still not gone. Br J Psychiatry 196(2):92–95. https://doi.org/10.1192/bjp.bp.109.073429
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381(9875):1371–1379. https://doi.org/10.1016/S0140-6736(12)62129-1.Identification
Cuthbert BN, Insel TR (2013) Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med 11:126. https://doi.org/10.1186/1741-7015-11-126
Gejman PV, Sanders AR, Duan J (2010) The role of genetics in the etiology of schizophrenia. Psychiatr Clin N Am 33(1):35–66. https://doi.org/10.1016/j.psc.2009.12.003
Geschwind DH, Flint J (2015) Genetics and genomics of psychiatric disease. Science 349(6255):1489–1494. https://doi.org/10.1126/science.aaa8954.Genetics
Goghari VM, Sponheim SR (2008) Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder. Schizophr Res 103(1–3):186–191. https://doi.org/10.1016/j.schres.2008.05.015
Gottesman IGT, Gould TD (2003) The Endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160(4):636–645
Greenwood TA, Shutes-David A, Tsuang D (2019) Endophenotypes in schizophrenia: digging deeper to identify genetic mechanisms. J Psychiatry Brain Sci 4(2):1–26. https://doi.org/10.20900/jpbs.20190005
Halvorsen M et al (2020) Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia. Nature Commun. Springer US 11(1):1842. https://doi.org/10.1038/s41467-020-15707-w
Hart AB et al (2014) Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder. Proc Natl Acad Sci U S A 111(16):5968–5973. https://doi.org/10.1073/pnas.1318810111
Hoffman GE et al (2017) Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nat Commun. Springer US 8(1):2225. https://doi.org/10.1038/s41467-017-02330-5
Ingraham LJ, Kety SS (2000) Adoption studies of schizophrenia. Am J Med Genet 97(1):18–22
Insel T et al (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatr 7(July):748–751. https://doi.org/10.1176/appi.ajp.2010.09091379
Keller MC, Visscher PM (2015) Genetic variation links creativity to psychiatric disorders. Nat Neurosci 18(7):928–929. https://doi.org/10.1038/nn.4047
Kety SS et al (1971) Mental illness in the biological and adoptive families of adopted schizophrenics. Am J Psychiatry 128(3):302–306
Khandaker GM et al (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2(3):258–270. https://doi.org/10.1016/S2215-0366(14)00122-9
Lam M et al (2019) Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat Genet 51:1670–1678. https://doi.org/10.1016/j.euroneuro.2018.08.019
Li J, Cai T, Jiang Y, Chen H, He X, Chen C, Li X, Shao Q, Ran X, Li Z, Xia K, Liu C, Sun ZS, Jinyu Wu J (2016) Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database. Mol Psychiatry 21(2):290–297
Liang SG, Greenwood TA (2015) The impact of clinical heterogeneity in schizophrenia on genomic analyses. Schizophr Res 161:490–495
Lilienfeld SO, Treadway MT (2016) Clashing diagnostic approaches: DSM-ICD versus RDoC. Annual review of clinical psychology. Annu Rev Clin Psychol 12:435–463. https://doi.org/10.1146/annurev-clinpsy-021815-093122.Clashing
Lin M et al (2016) Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion. BMC Syst Biol 10(1):1–20. https://doi.org/10.1186/s12918-016-0366-0
Maier R et al (2015) Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder. Am J Hum Genet 96(2):283–294. https://doi.org/10.1016/j.ajhg.2014.12.006
Malhotra D, Sebat J (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell (Elsevier Inc.) 148(6):1223–1241. https://doi.org/10.1016/j.cell.2012.02.039
Manchia M et al (2013) The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases. PLoS One 8(10):1–7. https://doi.org/10.1371/journal.pone.0076295
National Human Genomics Research institute Talking Glossary (n.d.). Available at: https://www.genome.gov/genetics-glossary. Accessed: 20 April 2020
Ng SB et al (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461(7261):272–276. https://doi.org/10.1038/nature08250
Nica AC, Dermitzakis ET (2013) Expression quantitative trait loci: resent and future. Philos Trans R Soc Lond B Biol Sci 368(1620):20120362. https://doi.org/10.1098/rstb.2012.0362
O’Bleness M, Searles VB, Varki A, Gagneux P, Sikela JM (2012) Evolution of genetic and genomic features unique to the human lineage. Nat Rev Genet 13(12):853–866. https://doi.org/10.1038/nrg3336.Evolution
Pardiñas AF et al (2018) Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet 50(3):381–389. https://doi.org/10.1038/s41588-018-0059-2
Paşca SP et al (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17(12):1657–1662. https://doi.org/10.1038/nm.2576
Patel KR et al (2014) Schizophrenia: overview and treatment options. P T 39(9):638–645
Power RA, Steinberg S, Bjornsdottir G, Rietveld CA, Abdellaoui A, Nivard MM, Johannesson M, Galesloot TE, Hottenga JJ, Willemsen G, Cesarini D, Benjamin DJ, Magnusson PK, Ullén F, Tiemeier H, Hofman A, van Rooij FJ, Walters G, Sigurdsson E, Tho K (2015) Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nat Neurosci 18(7):953–955
Rajarajan P et al (2018) Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science 362(6420):eaat4311. https://doi.org/10.1126/science.aat4311
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421–427. https://doi.org/10.1038/nature13595
Schrode N et al (2019) Synergistic effects of common schizophrenia risk variants. Nat Genet 51(10):1475–1485. https://doi.org/10.1038/s41588-019-0497-5
Sekar A et al (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530(7589):177–183. https://doi.org/10.1038/nature16549
Shcheglovitov A et al (2013) SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved 503(7475):267–271. Available at: https://doi.org/10.1038/nature12618
Shorter E (2009) The history of lithium therapy. Bipolar Disord 11(Suppl 2):4–9
Song J et al (2016) Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder. Mol Psychiatry 21(9):1290–1297. https://doi.org/10.1038/mp.2015.165
Stem Cell Information Home Page. In Stem Cell Information [World Wide Web site] (2016). Available at: https://stemcells.nih.gov/info/basics/6.htm. Accessed: 20 April 2020
Stern S et al (2018) Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry (Nature Publishing Group) 23(6):1453–1465. https://doi.org/10.1038/mp.2016.260
Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60(12):1187–1192. https://doi.org/10.1001/archpsyc.60.12.1187
Sullivan PF et al (2018) Psychiatric genomics: an update and an agenda. Am J Psychiatr 175(1):15–27. https://doi.org/10.1176/appi.ajp.2017.17030283
Szabo Q, Bantignies F, Cavalli G (2019) Principles of genome folding into topologically associating domains. Sci Adv 5(4):eaaw1668. https://doi.org/10.1126/sciadv.aaw1668
Szöke A, Pignon B, Schürhoff F (2019) Schizophrenia risk factors in exceptional achievers: a re-analysis of a 60-year-old database. Sci Rep 9(1):1294. https://doi.org/10.1038/s41598-018-37484-9
Teslovich TM et al (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466(7307):707–713. https://doi.org/10.1038/nature09270
Topol A et al (2016) Dysregulation of miRNA-9 in a subset of schizophrenia patient-derived neural progenitor cells. Cell Rep (ElsevierCompany) 15(5):1024–1036. https://doi.org/10.1016/j.celrep.2016.03.090
Vassos E et al (2017) An examination of polygenic score risk prediction in individuals with first-episode psychosis. Biol Psychiatry (Elsevier) 81(6):470–477. https://doi.org/10.1016/j.biopsych.2016.06.028
Voisey J et al (2011) A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study. Behav Brain Funct 7(1):51. https://doi.org/10.1186/1744-9081-7-51
Walss-Bass C, Fries GR (2019) Are lithium effects dependent on genetic/epigenetic architecture? Neuropsychopharmacology (Nature Publishing Group) 44(1):228. https://doi.org/10.1038/s41386-018-0194-6
Webber C (2017) Epistasis in Neuropsychiatric Disorders. Trends Genet (Elsevier Ltd) 33(4):256–265. https://doi.org/10.1016/j.tig.2017.01.009
Wen Z et al (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515(7527):414–418. https://doi.org/10.1038/nature13716
Wray NR, Goddard ME, Visscher PM (2007) Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res 17(10):1520–1528. https://doi.org/10.1101/gr.6665407
Zubieta J-K et al (2003) COMT genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299(5610):1240–1243. https://doi.org/10.1126/science.1078546
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Melnick, L. (2021). Neurogenomics with Application to Schizophrenia and Other Major Neuropsychiatric Diseases with Complex Heredity. In: Schreiber, R. (eds) Modern CNS Drug Discovery . Springer, Cham. https://doi.org/10.1007/978-3-030-62351-7_3
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