\nGenome-wide association analysis identifies 13 new risk loci for schizophrenia<\/a>.<\/div>\nby Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, Bergen SE, Collins AL, Crowley JJ, Fromer M, Kim Y, Lee SH, Magnusson PK, Sanchez N, Stahl EA, Williams S, Wray NR, Xia K, Bettella F, Borglum AD, Bulik-Sullivan BK, Cormican P, Craddock N, de Leeuw C, Durmishi N, Gill M, Golimbet V, Hamshere ML, Holmans P, Hougaard DM, Kendler KS, Lin K, Morris DW, Mors O, Mortensen PB, Neale BM, O’Neill FA, Owen MJ, Milovancevic MP, Posthuma D, Powell J, Richards AL, Riley BP, Ruderfer D, Rujescu D, Sigurdsson E, Silagadze T, Smit AB, Stefansson H, Steinberg S, Suvisaari J, Tosato S, Verhage M, Walters JT; Multicenter Genetic Studies of Schizophrenia Consortium, Levinson DF, Gejman PV, Kendler KS, Laurent C, Mowry BJ, O’Donovan MC, Owen MJ, Pulver AE, Riley BP, Schwab SG, Wildenauer DB, Dudbridge F, Holmans P, Shi J, Albus M, Alexander M, Campion D, Cohen D, Dikeos D, Duan J, Eichhammer P, Godard S, Hansen M, Lerer FB, Liang KY, Maier W, Mallet J, Nertney DA, Nestadt G, Norton N, O’Neill FA, Papadimitriou GN, Ribble R, Sanders AR, Silverman JM, Walsh D, Williams NM, Wormley B; Psychosis Endophenotypes International Consortium, Arranz MJ, Bakker S, Bender S, Bramon E, Collier D, Crespo-Facorro B, Hall J, Iyegbe C, Jablensky A, Kahn RS, Kalaydjieva L, Lawrie S, Lewis CM, Lin K, Linszen DH, Mata I, McIntosh A, Murray RM, Ophoff RA, Powell J, Rujescu D, Van Os J, Walshe M, Weisbrod M, Wiersma D; Wellcome Trust Case Control Consortium 2; Management Committee:, Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin AP, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW; Data and Analysis Group:, Spencer CC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson RD, Strange A, Su Z, Vukcevic D, Donnelly P; DNA, Genotyping, Data QC and Informatics Group:, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Tashakkori-Ghanbaria A, Waller MJ, Weston P, Widaa S, Whittaker P, Barroso I, Deloukas P; Publications Committee:, Mathew CG, Blackwell JM, Brown MA, Corvin AP, McCarthy MI, Spencer CC, Bramon E, Corvin AP, O’Donovan MC, Stefansson K, Scolnick E, Purcell S, McCarroll SA, Sklar P, Hultman CM, Sullivan PF.<\/div>\nNature Genetics<\/font><\/strong>. 2013 Aug 25. doi: 10.1038\/ng.2742. [Epub ahead of print]<\/div>\n<\/p>\n
Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study [GWAS] for schizophrenia beginning with a Swedish national sample [5,001 cases and 6,243 controls] followed by meta-analysis with previous schizophrenia GWAS [8,832 cases and 12,067 controls] and finally by replication of SNPs in 168 genomic regions in independent samples [7,413 cases, 19,762 controls and 581 parent-offspring trios]. We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs [95% credible interval of 6,300-10,200 SNPs] contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.<\/div>\n<\/blockquote>\nGenetic studies of patients with psychiatric illnesses are beginning to be published with increasing frequency, and I don’t know what they mean. Everything about this study is huge. It involved about 60,000 subjects, about a third identified as having chronic schizophrenia and two thirds being controls [even the author count is huge at 67]. It’s hard for a mortal to read the paper and understand even how the analysis is done. They located twenty-two SNPs statistically associated with schizophrenia, thirteen previously unidentified. But when they say things like this, my eyes begin to cross:<\/div>\n\nWe estimate that 8,300 independent, mostly common SNPs [95% credible interval of 6,300-10,200 SNPs] contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability.<\/div>\n<\/blockquote>\nAnd when they end with:<\/div>\n\nCommon genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.<\/div>\n<\/blockquote>\nlike 60,000 is some kind of pilot project, I find myself speechless at larger studies<\/em>. It’s not what many thought, looking for the<\/u> schizophrenia gene. It’s 8,300 independent, mostly common SNPs<\/em> … to account for 32% of the variance<\/em>. Like 22 down, 8,278 to go? I’m not trying to poke fun about that. It is whatever it is. But there are a few points worth making. This is obviously a very complex task, and the answers to be found are well down the road. Whatever the methodologies for generating this data and analyzing it, the mechanisms for validation are going to be a huge task as well, requiring a lot of expertise. As an aside, I would doubt that the ongoing projects like iSPOT or EMBARC proposing to find genetic markers that predict antidepressants response have sufficient power for success. I’m unaware of any strong evidence that points to their existence in the first place, but even if there were, the size of the cohort needed to find it would likely be much larger than these studies. A second point has to do with translation. This, from the paper: <\/div>\n\nOur GWAS for schizophrenia suggests candidate genes involved in calcium channels. A calcium channel functional complex has also been suggested as a mechanism in the etiology of bipolar disorder and autism. These results suggest hypotheses for clinical translation. Multiple approved medications act at calcium channels, including some antipsychotics [for example, pimozide] along with adjuvants for treatment non-response for schizophrenia and bipolar disorder [for example, the calcium channel blockers verapamil and nifedipine]. It is possible that drugs that act on the protein products of CACNA1C and CACNB2 for a different therapeutic indication could be repurposed for the treatment of schizophrenia…<\/div>\n<\/blockquote>\nThe whole idea of translation<\/em>, speeding drugs from the bench to the bedside, seems out of sync with where we are right now, either in psychiatry or our understanding of psychotic illness. Finding SNPs that separate from placebo may well be a genuine advance in the quest to explain the familial factors in psychosis, but it sure doesn’t help understand what the 8,300 SNPs estimate means. And the track record of genetic studies of this type is that they frequently don’t pass the test of independent replication. We all know that the pressure of the NIMH\/psychiatry translational<\/em> agenda has been heightened by the "empty pipeline" of CNS drugs from the pharmaceutical industry.<\/div>\n<\/p>\n
The balance between restraint and exuberance in psychiatric drug research has been out of whack for a long time. We’re barely on the edge of catching up on the restraint side with the push for data transparency in clinical trials and the focus on gross scientific misbehavior on the part of industry and people in our own ranks. But these genetic studies involve technologies and sample sizes that call for really specialized skills and resources to vet <\/em>– no task for old men with Excel Spreadsheets. We mere mortals wouldn’t know where to start. Right now, I would prefer that the NIMH Director be writing a blog that discussed how we are going to insure that the data coming out of these genetic studies is vetted<\/em> and revetted <\/em>and its implications are very carefully evaluated instead of saying this [In Vitro Veritas?<\/a>]:<\/div>\n\nOver the past 6 months we have turned a corner in our studies of the genetic basis of schizophrenia and autism. For years the field of psychiatric genetics has struggled: family and twin studies demonstrated that these disorders were heritable, but findings from small studies reporting specific risk genes could not be replicated. With larger samples and better tools, we have gone from famine to feast, with almost too many genetic findings to follow up. A new report has just described 13 new genetic findings associated with schizophrenia, resulting in over 100 common variants now identified as risk factors…<\/div>\n<\/blockquote>\nBoth Dr. Insel and the army of authors and scientists involved in this work have every reason to be excited with these findings. But that’s all the more reason for caution. The track record in the search for magic bullets<\/em> in psychiatry is nothing to get excited about, and the borrowed concept, translation<\/em>, may actually be the opposite of what is needed here. In the past, the desperateness of the patient’s illnesses and the expense of care were forces pushing reckless treatment. In recent decades, the pressure of ideology and commercial profit have been added to the mix. This article had too much speculation about implications and not enough talk about plans for replication to my liking. And Dr. Insel’s blog was more in the range of the charge of the light brigade than the kind of strategizing we need from the NIMH about how to validate and proceed with the new science of genomics. It’s the National Institute of Mental Health, not the National Institute of Drug Discovery [or the National Institute of Clinical Neuroscience]…<\/div>\n","protected":false},"excerpt":{"rendered":"Genome-wide association analysis identifies 13 new risk loci for schizophrenia. by Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, Bergen SE, Collins AL, Crowley JJ, Fromer M, Kim Y, Lee SH, Magnusson PK, Sanchez N, Stahl EA, Williams S, Wray NR, Xia K, Bettella F, Borglum AD, Bulik-Sullivan BK, Cormican P, […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_topic_count_hidden":0,"_bbp_reply_count_hidden":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-40239","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/40239","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=40239"}],"version-history":[{"count":10,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/40239\/revisions"}],"predecessor-version":[{"id":40249,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/40239\/revisions\/40249"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=40239"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=40239"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=40239"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}