Ethnicity‐Based Differences in the Association of LOXL1 Polymorphisms with Pseudoexfoliation/Pseudoexfoliative Glaucoma: A Meta‐Analysis

Pseudoexfoliation (PEX) is an age‐related disorder of the extracellular matrix; it is strongly associated with glaucoma, the leading cause of irreversible blindness worldwide. We conducted an ethnic‐based meta‐analysis of the association of LOXL1 polymorphisms with PEX/pseudoexfoliative glaucoma (PEXG). Association studies were retrieved systematically from PubMed, EMBASE, and Web of Knowledge. Allelic and genotype frequencies of rs3825942, rs1048661, and rs2165241 were compared between PEX/PEXG and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model. Overall, 39 independent cohorts were included. Rs3825942 (G) was an at risk allele for PEX/PEXG in Caucasians, Japanese, Koreans, Chinese, South Asians, and Middle Easterners, but protective in Black South Africans (OR = 0.10, 95%CI:0.06–0.16). Rs1048661 (G) was an at risk allele for PEX/PEXG in Caucasians, South Asians, Middle Easterners and Black South Africans, but was protective in Japanese (OR = 0.03, 95%CI:0.02–0.06) and Koreans (OR = 0.10, 95%CI:0.05–0.22). These associations we‐re confirmed for the genotypic recessive models. Rs2165241 (C) was a protective allele for PEX/PEXG in Caucasians, but was an at risk allele in Japanese (OR = 7.49, 95%CI:3.22–17.41) and Koreans (OR = 6.63, 95%CI:2.60–16.90). This was confirmed for the genotypic dominant model. Other genetic and/or environmental factors may modify the effect of LOXL1 polymorphisms in certain ethnic groups.     

No evidence of association of FLJ10986 and ITPR2 with ALS in a large German cohort

A recent genome-wide association study (GWAS) found significant association of six single nucleotide polymorphisms (SNPs) in the gene FLJ10986 with sporadic amyotrophic lateral sclerosis (SALS). Another independent GWAS reported significant association of one SNP in the gene inositol 1,4,5-triphosphate receptor 2 (ITPR2) with SALS. These studies provided conflicting results. We examined the six most significant SNPs in FLJ10986 and one SNP in ITPR2 in a large cohort consisting of 595 SALS cases and 681 controls ascertained from Germany. Our results did not provide evidence for the association of these SNPs with SALS, suggesting a possible population-specific effect for FLJ10986 and ITPR2 that do not modulate the risk for SALS in the German population.     

Rapid inexpensive genome-wide association using pooled whole blood

Genome-wide association studies (GWAS) have now successfully identified important genetic variants associated with many human traits and diseases. The high cost of genotyping arrays in large data sets remains the major barrier to wider utilization of GWAS. We have developed a novel method in which whole blood from cases and controls, respectively, is pooled prior to DNA extraction for genotyping. We demonstrate proof of principle by clearly identifying the associated variants for eye color, age-related macular degeneration, and pseudoexfoliation syndrome in cohorts not previously studied. Blood pooling has the potential to reduce GWAS cost by several orders of magnitude and dramatically shorten gene discovery time. This method has profound implications for translation of modern genetic approaches to a multitude of diseases and traits yet to be analyzed by GWAS, and will enable developing nations to participate in GWAS.Genome-wide association studies (GWAS) have successfully identified single nucleotide polymorphisms (SNPs) associated with many human diseases (McCarthy et al. 2008). GWAS have broken a bottleneck in the understanding of common complex diseases as no a priori knowledge of underlying molecular mechanisms is required (McCarthy et al. 2008). The high cost of SNP arrays remains a major barrier to widespread utilization of such studies. Typically, arrays capable of genotyping 3 × 10⁵–1 × 10⁶ SNPs are analyzed for every case and control individually. GWAS generally utilize large data sets with DNA extraction followed by SNP array genotyping costs running to >US$1 million, accompanied by long-time requirements for genotyping. Uncertainty about the genetic architecture of a given trait or disease means there is no guarantee of a successful outcome despite the large investment required. Many groups researching diseases in developing nations, or traits of perceived lesser clinical significance, have been unable to pursue GWAS methodology due to the high budgets required. One strategy for reducing cost is equimolar pooling of separately extracted DNA samples (Macgregor et al. 2006; Pearson et al. 2007). Rather than individually genotyping each subject in the case and control cohorts, stringently quantitated equimolar DNA pools derived from all cases and all controls are constructed separately and then genotyped. Pool construction for this genotyping strategy is labor-intensive and requires sophisticated DNA quantitation procedures (Macgregor et al. 2008).We hypothesized that equal volume, but unquantitated whole blood aliquots, from case and control cohorts could be pooled prior to DNA extraction. Although this clearly introduces a potential error relative to pooling of DNA, by deriving a formula for the degree of error expected given typical cell count values, we show that the additional error is very small. The “pooling of blood” (POB) method imparts large savings in time, labor, arrays, and reagents. We provide strong proof of principle data indicating that POB-based GWAS can identify known genes for eye color, pseudoexfoliation syndrome, and for age-related macular degeneration (AMD), the commonest cause of blindness in the Western world. The POB approach is easily applied to array-based GWAS, which aim to identify common variants of small effect. However, with full-genome sequencing becoming an accessible commodity, the identification of rare causal variants of larger effect may also prove tenable using our novel POB method.     

Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients

Pseudoexfoliation (PEX) syndrome is a generalized disease of the extracellular matrix and the most common identifiable cause of open-angle glaucoma. Two single nucleotide polymorphisms in the lysyl oxidase-like 1 (LOXL1) gene (rs1048661 and rs3825942) have been recently identified as strong genetic risk factors for both PEX syndrome and PEX glaucoma. Here we investigated the expression and localization of LOXL1, LOXL2, and lysyl oxidase (LOX) in tissues of PEX syndrome/glaucoma patients and controls in correlation with their individual single nucleotide polymorphism genotypes and stages of disease. LOXL1 ocular expression was reduced by ~20% per risk allele of rs1048661, whereas risk alleles of rs3825942, which were highly overrepresented in PEX cases, did not affect LOXL1 expression levels. Irrespective of the individual genotype, LOXL1 expression was significantly increased in early PEX stages but was decreased in advanced stages both with and without glaucoma compared with controls, whereas LOX and LOXL2 showed no differences between groups. LOXL1 was also found to be a major component of fibrillar PEX aggregates in both intra- and extraocular locations and to co-localize with various elastic fiber components. These findings provide evidence for LOXL1 involvement in the initial stages of abnormal fibrogenesis in PEX tissues. Alterations of LOXL1 activation, processing, and/or substrate specificity may contribute to the abnormal aggregation of elastic fiber components into characteristic PEX fibrils.     

Association of the HLA region with multiple sclerosis as confirmed by a genome screen using >10,000 SNPs on DNA chips

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with a complex genetic background. Here, we present a genome screen for association in small scale, employing 11,555 single nucleotide polymorphisms (SNPs) on DNA chips for genotyping 100 MS patients stratified for HLA-DR2⁺ and 100 controls. More than 500 SNPs revealed significant differences between cases and controls before Bonferroni correction. A fraction of these SNPs was reanalysed in two additional cohorts of patients and controls, using high-throughput genotyping methods. A marker on chromosome 6p21.32 (rs2395182) yielded the highest significance level, validating the established HLA-DR association.P. Nürnberg and J.T. Epplen contributed equally.     

Comparison of genetic variation of breast cancer susceptibility genes in Chinese and German populations

Genome-wide association studies (GWAS) identified several genetic risk factors for breast cancer, however, most of them were validated among women of European ancestry. This study examined single-nucleotide polymorphisms (SNPs) contributing to breast cancer in Chinese (984 cases and 2206 controls) and German (311 cases and 960 controls) populations. Eighteen SNPs significantly associated with breast cancer, previously identified in GWAS were genotyped. Twelve SNPs passed quality control and were subjected to statistical analysis. Seven SNPs were confirmed to be significantly associated with breast cancer in the Chinese population, reflecting three independent loci (ESR1, FGFR2, TOX3) and five of these were also confirmed in the German population. The strongest association was identified for rs2046210 in the Chinese (odds ratio (OR)=1.42, 95% confidence interval (CI)=1.28–1.59, P=1.9 × 10⁻¹⁰) and rs3803662 in the German population (OR=1.43, 95% CI=1.17–1.74, P=4.01 × 10⁻⁴), located upstream of the ESR1 and TOX3 gene, respectively. For the first time, rs3757318 at 6q25.1, located next to the gene encoding estrogen receptor α (ESR1) was found to be strongly associated with breast cancer (OR=1.33, 95% CI=1.18–1.49, P=1.94 × 10⁻⁶) in the Chinese population. The frequency of this variant was markedly lower in the German population and the association was not significant. Despite the genetic differences, essentially the same risk loci were identified in the Chinese and the German populations. Our study suggested the existence of common genetic factors as well as disease susceptibility differences for breast cancer in both populations and highlighted the importance of performing comparison analyses for disease susceptibility within ethnic populations.     

A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals

We conducted a case–control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the APOC1 gene, achieved genome-wide significance (allele-based P = 1.8 × 10^?10). However, logistic regression analysis revealed that this association, which was replicated in an independent German sample, is fully explicable by linkage disequilibrium with the APOE allele ?4, the only variant hitherto established as a major genetic determinant of survival into old age. Our GWAS failed to identify any additional autosomal susceptibility genes. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power for a polygenic phenotype with loci of small effect such as human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE–longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity.     

Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ～327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.     

No association of DPP6 with amyotrophic lateral sclerosis in an Italian population

We have attempted to replicate a recently reported association of polymorphism rs10260404, in the Dipeptidyl-peptidase 6 gene (DPP6), with susceptibility to amyotrophic lateral sclerosis (ALS) in a large independent Italian cohort of 904 cases and 1036 controls. Minor allele frequency was 0.38 in cases and 0.39 in controls and no evidence of association with ALS was observed (P = 0.638). Our negative results agree with those recently reported in additional Polish and Italian cohorts.     

A case–control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE)

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p‐value = 6.24 × 10^?8), rs74477937 (p‐value = 8.56 × 10^?8) and rs78707086 (p‐value = 8.55 × 10^?8) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta‐analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.     

Genome-wide association study in German patients with attention deficit/hyperactivity disorder

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.     

Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans

Background

In this study, we investigated the role of the dipeptidyl-peptidase-6 (DPP6) gene in the etiopathogenesis of progressive forms of multiple sclerosis (PrMS).This gene emerged as a candidate gene in a genome-wide association study (GWAS) performed in an Italian sample of PrMS and controls in which two SNPs located in the gene (rs6956703 and rs11767658) showed evidence of association (nominal p-value < 10⁻⁴) (Martinelli-Boneschi et al.) [18]. Moreover, the gene is highly expressed in the central nervous system, and it has been found to be associated with sporadic cases of amyotrophic lateral sclerosis which shares some feature with PrMS.

Methods

We genotyped 19 SNPs selected using a direct and tagging approach in 244 Italian PrMS and 225 controls, and we measured the expression levels of the gene in 13 PrMS cases and 25 controls.

Results

Five out of 19 SNPs were found to be associated with the disease (adjusted p < 0.05), and they have been tested in an independent sample of 179 primary progressive MS and 198 controls from Northern Europe. None of the SNPs was replicated, but combined analysis confirmed the presence of association for rs2046748 (p = 2.5 × 10⁻³,OR = 1.82, 95%CI = 1.24–2.69).

Conclusions

These results, inflated by the limited sample size determined by the rarity of this condition, suggest a possible role of this gene in the susceptibility to PrMS, at least in Southern Europeans. Moreover, DPP6 was over-expressed in PrMS patients compared to controls.     

Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study

Background

A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt‐Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion‐like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND.

Methods

We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI‐TOF mass spectrometry.

Results

In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over‐represented or under‐represented in our cohort of patients with sCJD.

Conclusion

Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study.     

Association of GWAS loci with PD in China

Genome‐wide association studies (GWAS) have identified numerous single‐nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinson's disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case–control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS‐linked data and research on ethnic specific effect of common variants. © 2011 Wiley‐Liss, Inc.     

Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits,coronary artery disease and ischemic stroke

Recent genome-wide association studies (GWAS) have identified genetic variants associated with coronary artery disease (CAD), ischemic stroke (IS) and serum lipid traits in different ethnic groups. Some loci were found to affect the risk of CAD and IS. However, there were no data in the southern Chinese populations. Our study was to assess the association of CELSR2-PSRC1-SORT1 rs599839, rs464218 and rs6698443 SNPs and serum lipid levels and the risk of CAD and IS. The genotypes of 3 SNPs were detected in 561 CAD and 527 IS patients, and in 590 healthy controls. The genotypic and allelic frequencies of the rs599839 SNP were different between the controls and IS patients (P < 0.05). The minor G alleles of rs599839 and rs464218 SNPs were associated with higher high-density lipoprotein cholesterol concentrations in CAD and IS patients (P < 0.05); respectively. No association was found between the SNPs of rs599839, rs464218 and rs6698843 at the CELSR2-PSRC1-SORT1 and the risk of CAD or IS. These results will be replicated in the other Chinese populations.     

A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.     

Lack of association between rs3807989 in cav1 and atrial fibrillation

Background: A novel gene Caveolin-1(CAV1) was identified to be susceptibility to PR interval and also associated with atrial fibrillation (AF) in two Genome wide associations studies (GWAS) studies in European ancestry. The purpose of this study was to determine the association of the SNPs in CAV1 gene of rs3807989 with AF in Chinese Han patients. Methods and results: We attempted a replication in a cohort of 839 Chinese AF patients and 1215 healthy controls using melting temperature shift allele-specific genotyping analysis. One SNP in CAV1 (rs3807989) was genotyped. The final study cohort consisted of 839 AF patients and 1215 healthy controls. No significant association was detected between rs3807989 and AF in a Chinese Han population (allelic P-adj = 0.828 with OR = 1.02; genotypic P-adj = 0.815, 0.405, 0.760 with a dominant model, recessive model, and additive model). After logistic regression with multiple covariates, the association remained non-significant with adjusted P value 0.828. When the AF cases were further divided into lone AF (31.5%) and other types of AF (68.5%), no significant association was found between rs3807989 and lone AF (P-adj = 0.929 with OR = 0.990) and other types of AF (P-adj = 0.597 with OR = 1.060). Conclusion: The SNP rs3807989 in CAV1 gene is not associated with AF or lone AF in our studies, which suggests that the SNP rs3807989 in CAV1 may not be a risk factor for AF in Chinese Han population.     

Evaluation of risk loci for schizophrenia derived from genome‐wide association studies in a German population

In the genome‐wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053–1055] a UK‐sample of 479 cases with DSM‐IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK‐sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP‐marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P = 1.61 × 10^?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome‐wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93–1.26 95% CI) for the schizophrenia sample and 1.04 (0.90–1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta‐analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. © 2011 Wiley‐Liss, Inc.     

Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.