Monday, May 26, 2014

Three Papers, Three Different Schizophrenia Studies

A recent Wellcome Trust paper on human genetic variation focuses on positive selection for three genes, one of which is ZNF804A, a gene linked to schizophrenia.  To illustrate how complex the inter population interpretation of these genes can be, I reference three different papers which look at how schizophrenia genes play out in different populations.  The complexity of interpretation is likely beyond that of the public, and perhaps even beyond some in the research community.  The issue of the composition of the research teams does come into play here.  It is easy to see that the different research teams, each with their distinct interests, have their own interpretation of the effect of different schizophrenia genes.  The study and interpretation in these three papers are clearly not value and focus neutral.  In light of this, some of the broad statements made in the Wellcome Trust paper appear to be made rather cavalierly.

1.  Human genomic regions with exceptionally high or low levels of population differentiation identified from 911 whole-genome sequences
Vincenza Colonna, Qasim Ayub, Yuan Chen, et al.
bioRxiv posted online May 23, 2014
Access the most recent version at doi:
Lead author:  Wellcome Trust Sanger Institute

"Second, the derived allele at an exomic INDEL (a novel variant, Supplementary Table 2, chromosome 2, position 185802211) is an insertion of 3 bp (ACA) which adds a threonine residue at amino acid position 697 within the first exon of the zinc finger protein 804A gene(ZNF804A). This variant is present at high frequency in the ASN population (DAF=0.83 vs 0.58 and 0.07 in EUR and AFR, respectively). ZNF804A acts as a transcription factor and regulates the transcription of genes related to schizophrenia [41]. An intronic polymorphism (rs1344706) in this gene has been associated with schizophrenia [42] and a third variant, rs4667001 in the fourth exon, changes both an amino acid and mRNA levels [43]. The ACA insertion is in strong LD with rs4667001 (r^2 =0.96) but less so with rs1344706 (r^2= 0.45).  Because of the threonine insertion, the protein has an additional site for post-translational modifications such as glycosylation and phosphorylation. Phosphorylation of other proteins (e.g. the deubiquitinating enzyme OTUB1) has been demonstrated to regulate susceptibility
to pathogens of the Yersinia family [44], of which some members probably evolved in China[45], and thus we speculate that the insertion may have been selected in relation to pathogen resistance."

2.  Linkage analysis of schizophrenia in African-American families
HW Wiener, L Klei, [...], and RCP Go

"While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SibPal) and (2) treating only affected individuals as informative (using the program Merlin). We also explore three definitions of affected status: narrowly defined Schizophrenia; one broadened to include Schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26cM; Sibpal p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27cM; p from 0.0022 to 0.0000003); Merlin results support the significance of the Sibpal results (p = 0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia."

3. ZNF804A and schizophrenia susceptibility in Asian populations.
Li M, Shi CH, Shi YY, Luo XJ, Zheng XB, Li ZQ, Liu JJ, Chong SA, Lee J, Wang Y, Liu XY, Yin LD, Pu XF, Diao HB, Xu Q, Su B.
2012 Oct;159B(7):794-802.
Epub 2012 Aug 6.

"ZNF804A, a recently identified risk gene for schizophrenia, has been extensively investigated and the principle finding for this locus has been the association with SNP rs1344706 in populations of European ancestries. However, in Asian populations, only a few studies have been conducted for rs1344706 and the results were inconsistent. Here, we studied rs1344706 and schizophrenia susceptibility in multiple Asian case-control samples (10 Chinese and 2 Japanese samples; N = 21,062), and the meta-analyses indicated non-significant association of rs1344706 with schizophrenia (P = 0.26), suggesting the same SNP identified in European samples is not predisposing risk in Asians. Further genotyping and association analyses of a set of SNPs spanning the entire genomic region of ZNF804A (520 kb) identified no association except for SNP rs359895 (P = 7.8 x 10(-5) , N = 5,172), a newly reported risk SNP located in the ZNF804A promoter region with functional implications. This suggests that ZNF804A may also contribute to schizophrenia susceptibility in Asians although the risk SNP is different from that in Europeans, and it was supported by the detected up-regulation of ZNF804A mRNA expression in the blood cells of Chinese schizophrenia patients compared with normal controls (P = 0.004). Additionally, the linkage disequilibrium (LD) structure analyses using data from HapMap indicated distinct LD blocks across ZNF804A between Chinese and Europeans, which may explain the different association patterns between them, and also highlight the compounding difficulty of genetic studies of complex diseases like schizophrenia when studying multiple ethnic populations."

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