Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk.
paper
Cited
Public
- Authors
- Moskvina, V; Craddock, N; Holmans, P; Nikolov, I; Pahwa, J S; Green, E; Wellcome Trust Case Control Consortium; Owen, M J; O'Donovan, M C
- Year
- 2009
- Journal
- Molecular psychiatry
- PMID
- 19065143
- DOI
- 10.1038/mp.2008.133
- PMCID
- PMC3970088
Genome-wide association (GWAS) analyses have identified susceptibility loci for many diseases, but most risk for any complex disorder remains unattributed. There is therefore scope for complementary approaches to these data sets. Gene-wide approaches potentially offer additional insights. They might identify association to genes through multiple signals. Also, by providing support for genes rather than single nucleotide polymorphisms (SNPs), they offer an additional opportunity to compare the results across data sets. We have undertaken gene-wide analysis of two GWAS data sets: schizophrenia and bipolar disorder. We performed two forms of analysis, one based on the smallest P-value per gene, the other on a truncated product of P method. For each data set and at a range of statistical thresholds, we observed significantly more SNPs within genes (P(min) for excess<0.001) showing evidence for association than expected whereas this was not true for extragenic SNPs (P(min) for excess>0.1). At a range of thresholds of significance, we also observed substantially more associated genes than expected (P(min) for excess in schizophrenia=1.8 x 10(-8), in bipolar=2.4 x 10(-6)). Moreover, an excess of genes showed evidence for association across disorders. Among those genes surpassing thresholds highly enriched for true association, we observed evidence for association to genes reported in other GWAS data sets (CACNA1C) or to closely related family members of those genes including CSF2RB, CACNA1B and DGKI. Our analyses show that association signals are enriched in and around genes, large numbers of genes contribute to both disorders and gene-wide analyses offer useful complementary approaches to more standard methods.
Ranks achieved by genes based upon uncorrected single SNP and gene wide tests.Ranks are compared based upon uncorrected single SNP and gene wide tests for a) best p-value per gene and b) product of p-values truncated at β€ 0.01. A higher value corresponds to a more significant rank. Ranks were normalised to lie between 0 and 1. Figure 1a contains all analysed genes. Figure 1b contains only those 733 genes which have more than one SNP and at least one p-value β€ 0.01 (the threshold inclusion in the analysis).
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| Name | Type |
|---|---|
| ANK3 | gene |
| autism | phenotype |
| Bdnf | gene |
| Bipolar dataset local | cohort |
| bipolar disorder | phenotype |
| bipolar disorder GWAS local | cohort |
| CACNA1B local | gene |
| CACNA1C | gene |
| CAPN6 local | gene |
| case-control sample | cohort |
| CDC25B local | gene |
| Celera local | drug |
| Chromosome Reports data local | cohort |
| chromosomes 1-22 local | cohort |
| CMTM8 | gene |
| CNV | variant |
| common variants | cohort |
| complex diseases | phenotype |
| controls | cohort |
| copy number variants | variant |
| CSF2RA | gene |
| CSF2RB local | gene |
| CSF2 receptor local | drug |
| DAOA | gene |
| dbSNP | cohort |
| DFNB31 | gene |
| Dgkh | gene |
| DGKI local | gene |
| DISC1 | gene |
| disease | phenotype |
| DPP10 | gene |
| DTNBP1 | gene |
| Family based association sample local | cohort |
| functional variant | variant |
| gene | gene |
| gene boundaries local | gene |
| GeneChip 500K Mapping Array Set local | drug |
| genes | gene |
| genes surpassing p<0.001 local | gene |
| HLA | gene |
| human | cohort |
| human genome assembly build 36.2 local | cohort |
| interleukin receptor 3 local | drug |
| Interleukin receptor 3 local | drug |
| interleukin receptor 5 local | drug |
| Interleukin receptor 5 local | drug |
| LAMP3 local | gene |
| NCBI database local | cohort |
| neuropsychiatric disorders | phenotype |
| Nos1 | gene |
| NRG1 | gene |
| OPCML | gene |
| PALB2 local | gene |
| phenotype | phenotype |
| present bipolar dataset local | cohort |
| psychiatric disorders | phenotype |
| Psychoses | phenotype |
| psychosis | phenotype |
| rare variant | cohort |
| Reference sequence local | drug |
| RefSNPs local | variant |
| rheumatoid arthritis | phenotype |
| RNPEPL1 local | gene |
| RPGRIP1L local | gene |
| schizophrenia | phenotype |
| schizophrenia GWAS | cohort |
| seq_gene.md local | cohort |
| SIL1 local | gene |
| SNP | cohort |
| TDRD9 local | gene |
| Timothy syndrome | phenotype |
| TMEM108 local | gene |
| type 1 diabetes | phenotype |
| UK schizophrenia cases local | cohort |
| voltage-gated calcium channel | drug |
| Wellcome Trust case control consortium | cohort |
| WTCCC | cohort |
| WTCCC3 local | cohort |
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