Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes

Scripps Genomic Medicine and Scripps Translational Science Institute, La Jolla, California, United States of America.
PLoS Genetics (Impact Factor: 7.53). 06/2011; 7(6):e1002134. DOI: 10.1371/journal.pgen.1002134
Source: PubMed


Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10(-7)). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.

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    • "One caveat to the study of SNPs within non-genic regions is that, while it is known that common SNPs explain a substantial portion of heritability, not all SNPs contribute equally to the heritability of a trait. SNPs in genes explain the most heritability, while those near genes (or in areas regulating them) explain some, and those in non-genic regions (SNP deserts) explain little of the heritability (Smith et al., 2011; Yang et al., 2011; Schork et al., 2013). Despite this, it remains possible that SNPs located outside of coding regions represent a new class of regulatory SNPs that make an important contribution toward explaining heritability. "
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    ABSTRACT: Genome wide association studies are central to the evolution of personalized medicine. However, the propensity for single nucleotide polymorphisms (SNPs) to fall outside of genes means that understanding how these polymorphisms alter cellular function requires an expanded view of human genetics. Integrating the study of genome structure (chromosome conformation capture) into its function opens up new avenues of exploration. Changes in the epigenome associated with SNPs in gene deserts will allow us to define complex diseases in a much clearer manner, and usher in a new era of disease pathway exploration.
    Frontiers in Genetics 02/2014; 5:39. DOI:10.3389/fgene.2014.00039
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    • "In the case of positive associations with different SNPs in the same gene, we cannot exclude the replica value because haplotype-specific functional variations have not been analysed. A recent GWAS study on bipolar patients showed that there is likely common genetic variation associated with the disorder near exons (±10 kb) that could be identified in larger studies and also provided a framework for assessing the potential for replication when combining results from multiple studies [41]. "
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    ABSTRACT: Recent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase, DAO; D-amino acid oxidase activator, DAOA; protein phosphatase 3 catalytic subunit gamma isoform, PPP3CC; dystrobrevin-binding protein 1, DTNBP1) and schizophrenia susceptibility, even though with contrasting results. In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects. An association in the allele frequency was observed for the estimated PPP3CC CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (pcorrect = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82).Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in PPP3CC gene (pcorrect = 0.02, pcorrect = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the DAO gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the PPP3CC gene in females (p = 0.01, OR = 0.53, 95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For DTNBP1, we found a protective effect in males for the rs6459409 (pcorrect = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10-4, OR = 0.46, 95% CI: 0.30-0.70).In relation to diagnostic subtypes, the estimated/phased DAO GT diplotype and PPP3CC CAG triplotype female carriers were found to show relative risk ratio (RRR) values of 0.52 and 0.54 lower risk for a paranoid phenotype respectively. Although the results are preliminary and needed replication in a larger sample, this study suggests that NMDA receptor-mediated signalling genes (DAO, PPP3CC, DTNBP1) might be involved in schizophrenia pathogenic mechanisms related to gender.
    BMC Medical Genetics 03/2013; 14(1):33. DOI:10.1186/1471-2350-14-33 · 2.08 Impact Factor
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    • "Compared to SNPs randomly selected from the list of SNPs that were studied in the original genome-wide association study, the longevity-associated SNPs were much closer to coding SNPs (Figure 6C) and therefore this enrichment of coding mutations is not what we would expect by chance. Similar results were found in Smith et al. (2011). Based on this analysis, the two sequences appear to be enriched for coding mutations in close proximity to longevity-associated variants that were discovered through a genome-wide association study, and the results reinforce our hypothesis that exceptional longevity is determined by many longevity-associated variants that may counteract the effect of deleterious or disease-predisposing variants. "
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    ABSTRACT: Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age of 100 and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114 years old. We show that: (1) the sequence variant spectrum of these two individuals' DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to-date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for coding variants near longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity-associated variants that may counter the effects of disease-predisposing variants and extend lifespan. The continued analysis of the genomes of these and other rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme aging.
    Frontiers in Genetics 11/2011; 2:90. DOI:10.3389/fgene.2011.00090
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