Post by Former NIMH Director Thomas Insel: Psychiatric Genetics: More Pieces of the Puzzle
Two papers published online recently in Nature Genetics report results from the largest studies to date searching for genetic variants associated with schizophrenia and bipolar disorder. The findings are important. For schizophrenia, five new genetic loci are reported, including a variant in the microRNA gene, mir-137, which has previously been implicated in neurodevelopment – and two previously reported loci are confirmed. One of the confirmed loci is within the major histocompatibility complex (MHC), consistent with an immune component in schizophrenia risk. For bipolar disorder, the new report finds a locus in ODZ4 and, importantly, replicates a previous finding in the calcium channel gene, CACNA1C.
Psychiatric genetics has had its critics. Many early findings of candidate genes were not replicated. Genome-wide association studies, which look for associations in an unbiased search across the entire genome, failed to find anything significant in several early studies. And many critics wondered why there should be such an effort on genetics when the discovery of causative genes for “simple” genetic diseases, like Huntington’s disease, had not led to therapeutic breakthroughs. Even those who were sympathetic to genetics as a necessary step for developing a pathophysiology of mental illness, have been concerned about the heterogeneity of the diagnostic categories.
These new studies should allay some of these concerns. It’s important to realize that genome-wide association studies, which scan over a million common variants across the entire genome, identify risk factors, not causes of disease. In diabetes and inflammatory bowel disease, we now recognize scores of such risk factors, each contributing a small amount of risk, but in aggregate explaining a substantial share of the heritability of these disorders. For schizophrenia and bipolar disorder, which are syndromes with high heritability, genome-wide association studies have identified far fewer common risk variants Was this because there were few common variants contributing to mental disorders? Or were the studies not large enough?
The answer seems to be the size of the earlier studies. These new studies -- with 17,836 cases and 33,859 controls for schizophrenia and 11.974 cases and 51,792 controls for bipolar disorder -- are much larger than previous studies and finally we are seeing genetic risk factors emerge. The identified common variants are not causes of schizophrenia or bipolar disorder, but they suggest pathways and they may also reveal treatment targets. In diabetes, all of the current medications target pathways identified in genomic studies. There are many additional genetic findings which could indicate new medication targets. In schizophrenia and bipolar disorder, where we need new medication targets, none of the variants identify the presumed targets of current anti-psychotic drugs or mood stabilizers. Whether CACNA1C or mir-137 will lead to new therapies is now an empirical question.
But just as important as the results of these studies and the new pathways they reveal, these projects represent a new paradigm for the science of mental illness. Both studies are the products of the psychiatric genomics consortium (PGC), collaboration across more than 200 scientists in 65 institutions and 19 countries. These scientists and more than 100,000 research subjects have agreed to share data, so that we finally have the statistical power to scan across the entire genome, picking up changes in sequence which may increase risk. This broad sharing has been essential to progress in genetics, especially for common diseases where scores of variants, each contributing very slightly to risk, appear to interact in complex ways.
The PGC is also indicative of the reorientation of the psychiatric genomics community toward team science. In the team science approach, an entire community of investigators rallies around the idea of combining and leveraging intellectual and other resources (including data and samples) to answer a pressing scientific problem. Team Science as exemplified in the PGC not only leverages resources, but also creates a large platform from which new and cutting-edge science can be derived to move the entire field ahead.
What’s next? In addition to these subtle changes identified by these new papers on schizophrenia and bipolar disorder, much of the focus in psychiatric genetics has been the discovery of rare, structural changes in the chromosomes, which are far more common in mental disorders. With large numbers of patients and DNA samples, the next step will be putting these findings of rare and common variants together, finally getting the major pieces of the jigsaw puzzle we call mental disorders. From these and other studies, it already appears unlikely that the genetics will align with DSM disorders. Genetics may give us a different map of these disorders, based on neurodevelopmental processes. And, with luck, genetics can point us towards the next generation of treatments.
Genome-wide association study identifies five new schizophrenia loci .The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, Lin DY, Duan J, Ophoff RA, Andreassen OA, Scolnick E, Cichon S, St Clair D, Corvin A, Gurling H, Werge T, Rujescu D, Blackwood DH, Pato CN, Malhotra AK, Purcell S, Dudbridge F, Neale BM, Rossin L, Visscher PM, Posthuma D, Ruderfer DM, Fanous A, Stefansson H, Steinberg S, Mowry BJ, Golimbet V, De Hert M, Jönsson EG, Bitter I, Pietiläinen OP, Collier DA, Tosato S, Agartz I, Albus M, Alexander M, Amdur RL, Amin F, Bass N, Bergen SE, Black DW, Børglum AD, Brown MA, Bruggeman R, Buccola NG, Byerley WF, Cahn W, Cantor RM, Carr VJ, Catts SV, Choudhury K, Cloninger CR, Cormican P, Craddock N, Danoy PA, Datta S, de Haan L, Demontis D, Dikeos D, Djurovic S, Donnelly P, Donohoe G, Duong L, Dwyer S, Fink-Jensen A, Freedman R, Freimer NB, Friedl M, Georgieva L, Giegling I, Gill M, Glenthøj B, Godard S, Hamshere M, Hansen M, Hansen T, Hartmann AM, Henskens FA, Hougaard DM, Hultman CM, Ingason A, Jablensky AV, Jakobsen KD, Jay M, Jürgens G, Kahn RS, Keller MC, Kenis G, Kenny E, Kim Y, Kirov GK, Konnerth H, Konte B, Krabbendam L, Krasucki R, Lasseter VK, Laurent C, Lawrence J, Lencz T, Lerer FB, Liang KY, Lichtenstein P, Lieberman JA, Linszen DH, Lönnqvist J, Loughland CM, Maclean AW, Maher BS, Maier W, Mallet J, Malloy P, Mattheisen M, Mattingsdal M, McGhee KA, McGrath JJ, McIntosh A, McLean DE, McQuillin A, Melle I, Michie PT, Milanova V, Morris DW, Mors O, Mortensen PB, Moskvina V, Muglia P, Myin-Germeys I, Nertney DA, Nestadt G, Nielsen J, Nikolov I, Nordentoft M, Norton N, Nöthen MM, O'Dushlaine CT, Olincy A, Olsen L, O'Neill FA, Orntoft TF, Owen MJ, Pantelis C, Papadimitriou G, Pato MT, Peltonen L, Petursson H, Pickard B, Pimm J, Pulver AE, Puri V, Quested D, Quinn EM, Rasmussen HB, Réthelyi JM, Ribble R, Rietschel M, Riley BP, Ruggeri M, Schall U, Schulze TG, Schwab SG, Scott RJ, Shi J, Sigurdsson E, Silverman JM, Spencer CC, Stefansson K, Strange A, Strengman E, Stroup TS, Suvisaari J, Terenius L, Thirumalai S, Thygesen JH, Timm S, Toncheva D, van den Oord E, van Os J, van Winkel R, Veldink J, Walsh D, Wang AG, Wiersma D, Wildenauer DB, Williams HJ, Williams NM, Wormley B, Zammit S, Sullivan PF, O'Donovan MC, Daly MJ, Gejman PV. Nat Genet. 2011 Sep 18;43(10):969-976. doi: 10.1038/ng.940. PMID: 21926974
Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 . Psychiatric GWAS Consortium Bipolar Disorder Working Group, Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N, Edenberg HJ, Nurnberger JI Jr, Rietschel M, Blackwood D, Corvin A, Flickinger M, Guan W, Mattingsdal M, McQuillin A, Kwan P, Wienker TF, Daly M, Dudbridge F, Holmans PA, Lin D, Burmeister M, Greenwood TA, Hamshere ML, Muglia P, Smith EN, Zandi PP, Nievergelt CM, McKinney R, Shilling PD, Schork NJ, Bloss CS, Foroud T, Koller DL, Gershon ES, Liu C, Badner JA, Scheftner WA, Lawson WB, Nwulia EA, Hipolito M, Coryell W, Rice J, Byerley W, McMahon FJ, Schulze TG, Berrettini W, Lohoff FW, Potash JB, Mahon PB, McInnis MG, Zöllner S, Zhang P, Craig DW, Szelinger S, Barrett TB, Breuer R, Meier S, Strohmaier J, Witt SH, Tozzi F, Farmer A, McGuffin P, Strauss J, Xu W, Kennedy JL, Vincent JB, Matthews K, Day R, Ferreira MA, O'Dushlaine C, Perlis R, Raychaudhuri S, Ruderfer D, Hyoun PL, Smoller JW, Li J, Absher D, Thompson RC, Meng FG, Schatzberg AF, Bunney WE, Barchas JD, Jones EG, Watson SJ, Myers RM, Akil H, Boehnke M, Chambert K, Moran J, Scolnick E, Djurovic S, Melle I, Morken G, Gill M, Morris D, Quinn E, Mühleisen TW, Degenhardt FA, Mattheisen M, Schumacher J, Maier W, Steffens M, Propping P, Nöthen MM, Anjorin A, Bass N, Gurling H, Kandaswamy R, Lawrence J, McGhee K, McIntosh A, McLean AW, Muir WJ, Pickard BS, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Williamson R, Young AH, Ferrier IN, Stefansson K, Stefansson H, Thornorgeirsson T, Steinberg S, Gustafsson O, Bergen SE, Nimgaonkar V, Hultman C, Landén M, Lichtenstein P, Sullivan P, Schalling M, Osby U, Backlund L, Frisén L, Langstrom N, Jamain S, Leboyer M, Etain B, Bellivier F, Petursson H, Sigur Sson E, Müller-Mysok B, Lucae S, Schwarz M, Schofield PR, Martin N, Montgomery GW, Lathrop M, Oskarsson H, Bauer M, Wright A, Mitchell PB, Hautzinger M, Reif A, Kelsoe JR, Purcell SM. Nat Genet. 2011 Sep 18;43(10):977-83. doi: 10.1038/ng.943. PMID: 21926972