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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Schizophr Res. Author manuscript; available in PMC 2013 January 27.
Published in final edited form as:
PMCID: PMC3556386

On schizophrenia as a “disease of humanity”

T. Bernard Bigdeli, Ayman H. Fanous, Brien P. Riley, Mark Reimers, The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, Xiangning Chen, Kenneth S. Kendler, and Silviu-Alin Bacanu*

Schizophrenia (SCZ) is a debilitating neuropsychiatric syndrome of unknown etiology with a lifetime prevalence of 4–5 per 1000 (McGrath et al., 2008). Its evolutionary persistence, in spite of a marked reproductive disadvantage, and the nearly uniform incidence of SCZ worldwide, seem to point to a component of human genetic variation common to all populations (Huxley et al., 1964; Jablensky et al., 1992). If SCZ represents a “disease of humanity”, this could presuppose a role for variation associated with the speciation event(s) giving rise to Homo sapiens (Crow, 1997). It follows that the causal variants might reside in “genes” under selective pressure in the human or, to a lesser extent, primate lineages. Until recently, our ability to evaluate this hypothesis was limited by the resolution of comparative genomic studies. However, a newly published cross-species analysis has revealed numerous regions exhibiting signatures of rapid evolution in the human and primate lineages (Lindblad-Toh et al., 2011). Genes harboring or nearby these regions are enriched for immunity, developmental and, intriguingly, brain-related functions including axon guidance, extracellular signaling and receptor activity (Lindblad-Toh et al., 2011). We evaluate empirically the “disease of humanity” hypothesis by testing whether these 562 human-accelerated regions (HARs) and 576 primate-accelerated regions (PARs) are enriched for SCZ association signals.

Genome wide association studies (GWAS) represent a powerful, unbiased approach to the study of common genetic variation in complex human disease. Besides a modest number of statistically-significant signals, large GWAS are also known to yield many additional small and moderately-sized signals distributed over the genome (Purcell et al., 2009). Variants mapping to causal pathways are expected to show a substantial enrichment in smaller p-values. Thus, observing a significant enrichment in small p-values for a putatively causal pathway supports the validity of the hypothesis, while failure to do so casts doubt on the pathway’s relevance to the trait of interest.

We evaluate the strength of the “disease of humanity” hypothesis by testing whether single nucleotide polymorphisms (SNPs) mapping to HARs and PARs are significantly enriched in low p-values from the discovery phase (n = 21,856) of the Psychiatric GWAS Consortium (PGC) GWAS of SCZ (Ripke et al., 2011). To achieve this goal, we used the summary statistics for the 1.25 million SNPs reported by the consortium. Additionally, we considered the possibility of enrichment of HARs/PARs in low p-values from GWAS of bipolar disorder (BD) (Sklar et al., 2011) and major depressive disorder (MDD) (Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, 2012). Enrichment was assessed using (i) SNPs falling within HARs/PARs and (ii) the previous set of SNPs with the addition of the closest SNP within 25 kb of a HAR/PAR having no SNPs mapping to within its bounds. Mappings of SNPs to HARs/PARs were based on physical positions (hg18) reported by the 29 Mammals Project (

Of critical importance is how best to test for enrichment when the distribution of effect sizes of SNPs in pathways can vary widely between a few large signals and many smaller ones. Because no single test is expected to have optimal power across such a large parametric space, we employed two complementary approaches: i) Simes test and ii) sum of squares test (SST). Intuitively, the Simes test is useful for detecting pathways containing a few larger effects. Alternatively, SST is better suited to detecting pathways containing a greater number of small effects. The statistical significance of SST was assessed via 50,000 permutations using linkage disequilibrium information for European subjects from the 1000 Genomes Project (Durbin et al., 2010).

Because large GWAS are expected to yield an excess of small p-values (Purcell et al., 2009), a pathway consisting of randomly chosen SNPs might still exhibit significant enrichment under the weaker (self-contained) null hypothesis of no association. Therefore, we tested the stronger (competitive) null hypothesis of HARs/PARs enrichment above the PGC background. We found that SNPs mapping to HAR and PAR regions were not enriched in small p-values irrespective of disorder or statistical test applied (Table 1). Even when testing against the weaker null hypothesis of no association, we found slight enrichment (Simes p-value = 0.01) only for PARs in BD when including the most proximal SNP within 25 kb (data not shown). The arguably more-relevant HARs were not enriched in low p-values even under the weaker null hypothesis.

Table 1
Results for testing enrichment in low p-values of HAR and PAR.

The human- and primate-accelerated regions of evolutionary constraint reported by Lindblad-Toh et al. are not detectably enriched in SCZ causal variants. However, as noted by the authors, SNPs were found in fewer numbers and were of lower allele frequency in/near these constrained elements. Thus, the power to detect unobserved causal variants in using common SNPs may be limited for these regions. A more comprehensive approach might jointly consider rarer and structural variants together with common variants. Nonetheless, such a treatment awaits the more distant availability of data from very large sequencing studies.


We thank the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium and the 29 Mammals Project, who provided the data necessary for our analysis.

Role of funding source The funding source was not involved in designing or interpreting the study.


Contributors KSK, BPR, AHF, SAB, TBB, XC, and MR designed the study. TBB and SAB undertook the statistical analyses. TBB wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest All authors declare that they have no conflicts of interest.


  • Crow TJ. Is schizophrenia the price that Homo sapiens pays for language? Schizophr. Res. 1997;28:127–141. [PubMed]
  • Durbin RM, Abecasis GR, Altshuler DL, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from populationscale sequencing. Nature. 2010;467:1061–1073. [PMC free article] [PubMed]
  • Huxley J, Mayr E, Osmond H, Hoffer A. Schizophrenia as a genetic morphism. Nature. 1964;204:220–221. [PubMed]
  • Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A. Schizophrenia: manifestations, incidence and course in different cultures. a world health organization ten-country study. Psychol. Med. Monogr. Suppl. 1992:1–97. [PubMed]
  • Lindblad-Toh K, Garber M, Zuk O, Lin MF, Parker BJ, Washietl S, Kheradpour P, Ernst J, Jordan G, Mauceli E, Ward LD, Lowe CB, Holloway AK, Clamp M, Gnerre S, Alfoldi J, Beal K, Chang J, Clawson H, Cuff J, Di Palma F, Fitzgerald S, Flicek P, Guttman M, Hubisz MJ, Jaffe DB, Jungreis I, Kent WJ, Kostka D, Lara M, Martins AL, Massingham T, Moltke I, Raney BJ, Rasmussen MD, Robinson J, Stark A, Vilella AJ, Wen J, Xie X, Zody MC, Baldwin J, Bloom T, Chin CW, Heiman D, Nicol R, Nusbaum C, Young S, Wilkinson J, Worley KC, Kovar CL, Muzny DM, Gibbs RA, Cree A, Dihn HH, Fowler G, Jhangiani S, Joshi V, Lee S, Lewis LR, Nazareth LV, Okwuonu G, Santibanez J, Warren WC, Mardis ER, Weinstock GM, Wilson RK, Delehaunty K, Dooling D, Fronik C, Fulton L, Fulton B, Graves T, Minx P, Sodergren E, Birney E, Margulies EH, Herrero J, Green ED, Haussler D, Siepel A, Goldman N, Pollard KS, Pedersen JS, Lander ES, Kellis M. A high-resolution map of human evolutionary constraint using 29 mammals. Nature. 2011;478:476–482. [PMC free article] [PubMed]
  • Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry. 2012 (Electronic publication ahead of print) [PMC free article] [PubMed]
  • McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 2008;30:67–76. [PubMed]
  • Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–752. [PMC free article] [PubMed]
  • 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 CD, 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 HM, Jonsson EG, Bitter I, Pietilainen OP, Collier DA, Tosato S, Agartz I, Albus M, Alexander M, Amdur RL, Amin F, Bass N, Bergen SE, Black DW, Borglum 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 HL, 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, Glenthoj 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, Jurgens 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, Lonnqvist 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, Nothen 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, Rethelyi 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 OJ, van WR, 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. Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 2011;43:969–976. [PubMed]
  • 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, Zollner 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, Muhleisen TW, Degenhardt FA, Mattheisen M, Schumacher J, Maier W, Steffens M, Propping P, Nothen MM, Anjorin A, Bass N, Gurling H, Kandaswamy R, Lawrence J, McGhee K, McIntosh A, McLean AW, Muir WJ, Pickard BS, Breen G, St CD, 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, Landen M, Lichtenstein P, Sullivan P, Schalling M, Osby U, Backlund L, Frisen L, Langstrom N, Jamain S, Leboyer M, Etain B, Bellivier F, Petursson H, Sigur SE, Muller-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. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 2011;43:977–983. [PubMed]