When Seymour S. Kety accepted the challenge to lead the scientific endeavor of the National Institutes of Health dedicated to research in mental health, neurological disorders and stroke fifty years ago, he identified the unraveling of the causes of schizophrenia as one immediate and urgent aim. He devoted himself to this mission, directing a landmark study to elucidate the possible causes of this horrible mental disorder in Danish twins. Denmark happened to be the country with the most detailed health records on her citizens at the time. Dr. Kety can be heard commenting on the results of this pivotal research in a taped autobiographical interview available through the Society for Neuroscience. In this conversation, he was careful to point out that though the twin study had provided evidence for a genetic component in schizophrenia, other factors may play an equally important role in the disorder.
Half a century later, much has been learned about the changes in brain structure and function accompanying the symptoms of schizophrenia. Drugs have been developed that ameliorate these symptoms. Genes have been identified that encode proteins involved in the disorder. Last week, the journal Science electronically published the results of a major study authored by Walsh and others screening a large number of schizophrenic patients for small gene mutations. B. Carey commented on the findings in his article for The New York Times entitled "Study Hints of Gene Link to Risk of Schizophrenia" dated Mar. 28, 2008. The study has been published in print in Science Vol. 320. A plethora of genes was identified. How the products of these genes are precisely involved in the disorder remains to be examined. Notably, products of two sets of genes play a role in mechanisms crucial to brain development and function. One set is engaged in the growth of nerve cell connections during development. The other is involved in the action of glutamate.
Glutamate is the most prevalent excitatory neurotransmitter in the brain. Neurotransmitters are the chemical compounds that nerve cells use to transmit information. Glutamate is fundamental to the plasticity of nerve cell connections. Schizophrenic patients are known to contain unusually low levels of glutamate receptors in distinct areas of the cerebral cortex (Konradi and Heckers, 2003). The product of one gene that was found disrupted in schizophrenics, GRM7, affects a specific type of glutamate receptor on nerve cells known as metabotropic glutamate receptor mGluR5. Merck & Co. and Addex Pharmaceuticals currently develop a new generation of pharmaceuticals that modulate the action of glutamate at a subtype of this receptor and may ameliorate schizophrenia without enhancing the negative symptoms commonly observed with the currently available drugs.
Most significantly, however, the large number of genes identified in the study published in Science suggests that schizophrenia is the result of complex interactions among diverse processes in the brain. Despite this complexity, the observed mutations of genes crucial for brain development and function constitute intriguing findings. Nerve cells predominantly grow and establish connections with each other during brain development. They mostly transmit and process information in maturity. Nerve cells may respond to injury and loss of input in different fashion while they fulfill these two fundamentally distinct functions. During brain development, the points in time when control genes are activated play a particularly sensitive role. The proper ingredients have to come together at the right moment. Diversion from the schedule may result in deleterious consequences. Moreover, the influence of ambient stimuli and environmental factors comes to bear at critical junctures. The intricate interaction between the intrinsic clockwork of gene expression and extrinsic influences ultimately determines brain structure and function. Taking the temporal sensitivity of brain development into consideration, the observation that the symptoms of schizophrenia manifest themselves commonly at a specific age, i.e. in early adulthood, suggests that changes in the scheduling of developmental processes may play a fundamental role in the disorder.
The above interpretation also applies to another mental disorder that has attracted mounting attention (CNN, Apr. 1, 2008): autism. Autism has been diagnosed as early as in the second year of life. A genetic component is known to exist. Hallmeyer and others (2011) found a significant chance for twins to develop autism if one is diagnosed with the disorder and a high prevalence among males. The authors attribute this chance to genetic as well as epigenetic factors. However, the implicated genes remain elusive. Whereas the symptoms of schizophrenia are comparably narrowly defined, the symptoms of autism can range from mildly affected and highly intelligent to self-mutilating and mentally retarded. That is why the disorder is known today as Autism Spectrum disorder, or ASD for short. Because of this broad range, it seems even more unlikely than for schizophrenia that a common cause for autism can be found. However, the identification of the differences in brain mechanisms underlying autism may help to afford more effective individualized treatments.
- Jane Brody provides an informative update entitled "Trying Anything and Everything for Autism" of the therapeutic strategies parents currently pursue with their children in The New York Times on Jan. 19, 2009 (01/20/2009).
- Yesterday, National Public Radio's All Things Considered broadcast a segment entitled "Schizophrenia May be Linked to Immune System" on recent findings of genome-wide studies on the genetic background of schizophrenia. The studies are authored by the International Schizophrenia Consortium (2009) and Shi and others (2009) and were published online in the journal Nature this week. Kate Kelland reported on the results in her post entitled "Gene variation hinder mental illness tests: study" on Reuters and Nicholas Wade in his post entitled "Hoopla, and Disappointment, in Schizophrenia Research" for The New York Times, both dated Jul. 1, 2009. The methods used in both studies are similar to those employed in recent studies on the genetic background of autism. I have described the autism studies in an addendum to my post dated Jul. 11, 2008. The studies on schizophrenia report genetic variations associated with the disorder, attaining statistical significance when the genetic sequences of thousands of people with and without the disorder are compared. The researchers identified segments in the genetic code that showed statistically significant differences in sequence in the population of schizophrenic participants. The results are based on the grand averages across the populations of participants. That is, a single person may not possess the uncovered variations to any measurable degree. The differences are so small that they become detectable only in the sum of genetic sequences of large numbers of participants. The International Schizophrenia Consortium study demonstrated that small variations of tens of thousands of genes may additively contribute to a statistically significant effect in the disorder. The result constitutes no more than a long list of possibilities, the exact implementation of which remains yet unknown. Shi and others (2009) found that the greatest difference linked to schizophrenia pertains to genes encoding major histocompatibility complexes (MHCs) involved in our immune response. These genes exhibit great variability. The findings are associative. A causality remains to be established (07/02/09).
- Consistent with the findings of Shi and others (2009), Stefansson and others report in a letter to Nature published online this week that using genome-wide association methods they were able to identify in schizophrenic patients single nucleotide polymorphisms affecting genes involved in immune response (MHCs). In addition, the study implicates genes NRGN, playing a role in the stabilization of excitatory nerve cell connections during brain development, and TCF4, the product of which is a transcription factor (07/09/09).
- A genome-wide association study enrolling more than one thousand families with children diagnosed with ASD uncovered a single nucleotide polymorphism (SNP) statistically significantly associated with ASD on chromosome 5p15 between genes SEMA5A, involved in the growth of nerve cell connections, and TAS2R1, playing a role in gustation (Weiss and others, 2009). The expression of the former proved reduced in ASD (11/30/09).
- The genes NRG1 and ERBB4 have been implicated in schizophrenia (Li and others, 2006). Their products neuregulin 1, or NRG1 for short, and erbB-4, a tyrosine kinase receptor for NRG1, may influence the formation of connections among nerve cells in the cerebral cortex. In this week's issue of the journal Nature, Fazzari and others (2010) provide evidence in mice that both are instrumental in the development of inhibitory nerve cell circuits that use the neurotransmitter GABA and thereby indirectly influence the formation of excitatory connections using the neurotransmitter glutamate. Perhaps malfunctioning inhibition plays a more fundamental role in schizophrenia than previously thought (04/14/10).
- Green and others (2010) have accomplished to sequence the Neanderthal genome with extracts from fossilized bones of three female Neanderthals and compared this code to known genomes of modern humans. The comparison identified regions that underwent wide-ranging genetic code alterations. The regions contained genes NRG3, CADPS2 and AUTS2. Mutations in these genes have been associated with schizophrenia (NRG3, a member of neuregulin family, see above) and autism (CADPS2 and AUTS2). Their products are presumed to play a role in the differentiation of nerve cells, the formation of nerve cell connections and nerve cell function. The findings of Green and others (2010) suggest that these genes may contribute fundamentally to the mental abilities that distinguish modern humans from Neanderthals (05/07/10).
|Neandertal (courtesy M. Möller, Naturfreunde Düsseldorf)|
- The International Schizophrenia Consortium (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748-752.
- Fazzari P, Paternain AV, Valiente M, Pla R, Luján R, Lloyd K, Lerma J, Marín O, & Rico B (2010) Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature: advance online publication 14 April 2010 | doi:10.1038/nature08928.
- Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz H-Y M, Hansen NF, Durand EY, Malaspinas A-S, Jensen JD, Marques-Bonet T, Alkan C, Prüfer K, Meyer M, Burbano HA, Good JM, Schultz R, Aximu-Petri A, Butthof A, Höber B, Höffner B, Siegemund M, Weihmann A, Nusbaum C, Lander ES, Russ C, Novod N, Affourtit J, Egholm M, Verna C, Rudan P, Brajokovic D, Kucan Ž, Gušic I, Doronichev VB, Golovanova LV, Lalueza-Fox C, de la Rasilla M, Fortea J, Rosas A, Schmitz RW, Johnson PLF, Eichler EE, Falush D, Birney E, Mullikin JC, Slatkin M, Nielsen R, Kelso J, Lachmann M, Reich D, Pääbo, S (2010) A draft of the Neandertal Genome. Science 328: 710-722.
- Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N (2011) Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Arch Gen Psychiatry doi:10.1001/archgenpsychiatry.2011.76
- Li D, Collier DA, He L (2006) Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet 15: 1995–2002.
- Stefansson H, 87 others (2009). Common variants conferring risk of schizophrenia. Nature 460:744-747.
- Konradi C, Heckers S (2003) Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther 97:153-719.
- Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I, Dudbridge F, Holmans PA, Whittemore AS, Mowry BJ, Olincy A, Amin F, Cloninger CR, Silverman JM, Buccola NG, Byerley WF, Black DW, Crowe RR, Oksenberg JR, Mirel DB, Kendler KS, Freedman R, Gejman PV (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460:753-757.
- Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J (2008) Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia. Science 320:539-543.
- Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802-808.
Autism & Genes, Revisited
Fundamental Research & Fragile X Syndrome