Schizophrenia Research Forum - A Catalyst for Creative Thinking


Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012 Sep 7 ; 337(6099):1190-5. Pubmed Abstract

Comments on News and Primary Papers


Primary Papers: Systematic localization of common disease-associated variation in regulatory DNA.

Comment by:  Patrick Sullivan, SRF Advisor
Submitted 12 September 2012
Posted 12 September 2012

This Science paper has bearing on the genomic basis of complex traits, including schizophrenia, autism, and bipolar disorder(Maurano et al., 2012). A related paper in Nature will be of great interest to genomicists (ENCODE Project Consortium, 2012)

A major quandary in human genetics is how to understand the findings of genome-wide association studies for complex traits. This body of knowledge is now pretty huge: the NHGRI GWAS catalog (downloaded 22 June 2012, filtered for p < 1x10-8 and keeping the smallest p value if there were multiple SNP-trait pairs) contains genome-wide significant results for 2,441 SNPs, 385 traits, and 2,968 SNP-trait pairs from 672 papers. These associations are common (median minor allele frequency 0.29) and of subtle effect (median genotypic relative risk 1.19).

The diseases with the greatest number of associations are: Crohn's disease (94), ulcerative colitis (56), type 2 diabetes mellitus (56), type 1 diabetes mellitus (47), coronary artery disease (47), prostate cancer (45), and multiple sclerosis (42). Schizophrenia has 9 in this database, but current number is larger (see Sullivan et al., 2012) and, work in progress will push this number much higher.

The continuous traits with the greatest numbers of associations are: height (134 SNP associations), lipids (cholesterol HDL=75, LDL=60, total=58, and triglycerides=57), and body mass index (55).

At the same time, searches for rare, more actionable exonic variants have not yielded many hits, per 3 sizable studies of autism in Nature earlier this year (Sanders et al., 2012; O’Roak et al., 2012; Neale et al., 2012) , a recently published but smallish study for schizophrenia (Need et al., 2012), and, for what it's worth, unpublished results for T2DM. Several larger studies for schizophrenia are either in analysis or manuscript preparation, so the database for schizophrenia is not yet extensive.

One quandary with the GWAS results -- the major etiological clues for most complex disorders -- is that > 90% of these associations are not in regions that code for proteins. How does genetic variation act? What's the next step in the progression from DNA variation to ultimate disease phenotype?

The Science paper tells us that 76% of the GWAS hits above are either in or in high correlation with "DNase I hypersensitivity sites". Such sites tend to be stretches where DNA is more or less bare - unfolded, not pretzeled-up in histones, and open to transcription factors.

In addition, other work tells us that the GWAS hits tend to be "eQTLs" (expression quantitative trait loci, genetic variation that is strongly associated with the amounts of RNA from nearby genes).

Taken together, these studies provide a testable and now highly plausible general hypothesis: genomic regions implicated by GWAS act by regulating gene expression. If so, there is a distinct role for epigenetics.

Careful readers of SRF will have followed this debate (aka the rare "versus" common variant false dichotomy). The final word on this has yet to be written, but it is looking like the answers for complex traits like schizophrenia will be more related to subtle changes in expression in pathways than protein-killing mutations.

References:

References:

Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature . 2012 Sep 6 ; 489(7414):57-74. Abstract

Sullivan PF, Daly MJ, O'Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012 Jul 10;13(8):537-51. Abstract

Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sĕstan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012 April 5. Abstract

O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012 April 5. Abstract

Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook Jr EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012 April 5. Abstract

Need AC, McEvoy JP, Gennarelli M, Heinzen EL, Ge D, Maia JM, Shianna KV, He M, Cirulli ET, Gumbs CE, Zhao Q, Campbell CR, Hong L, Rosenquist P, Putkonen A, Hallikainen T, Repo-Tiihonen E, Tiihonen J, Levy DL, Meltzer HY, Goldstein DB. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet . 2012 Aug 10 ; 91(2):303-12. Abstract

View all comments by Patrick Sullivan