Genome-Wide Search for SNP Interactions in GWAS Data: Algorithm, Feasibility, Replication Using Schizophrenia Datasets.

In this study, we looked for potential gene-gene interaction in susceptibility to schizophrenia by an exhaustive searching for SNP-SNP interactions in 3 GWAS datasets (phs000021:phg000013, phs000021:phg000014, phs000167) using our recently published algorithm. The search space for SNP-SNP interaction was confined to 8 biologically plausible ways of interaction under dominant-dominant or recessive-recessive modes. First, we performed our search of all pair-wise combination of 729,454 SNPs after filtering by SNP genotype quality. All possible pairwise interactions of any 2 SNPs (5 × 1011) were exhausted to search for significant interaction which was defined by p-value of chi-square tests. Nine out the top 10 interactions, protein coding genes were partnered with non-coding RNA (ncRNA) which suggested a new alternative insight into interaction biology other than the frequently sought-after protein-protein interaction. Therefore, we extended to look for replication among the top 10,000 interaction SNP pairs and high proportion of concurrent genes forming the interaction pairs were found. The results indicated that an enrichment of signals over noise was present in the top 10,000 interactions. Then, replications of SNP-SNP interaction were confirmed for 14 SNPs-pairs in both replication datasets. Biological insight was highlighted by a potential binding between FHIT (protein coding gene) and LINC00969 (lncRNA) which showed a replicable interaction between their SNPs. Both of them were reported to have expression in brain. Our study represented an early attempt of exhaustive interaction analysis of GWAS data which also yield replicated interaction and new insight into understanding of genetic interaction in schizophrenia.

Estrogen receptor α polymorphisms and the risk of cognitive decline: A 2-year follow-up study.

OBJECTIVE: The neuroprotective role of estrogen is supported by biochemical studies, but the results from clinical trials of estrogen replacement therapy on cognitive decline are controversial. One possible missing link might be the interindividual difference in estrogen receptor expression. In this study, the association of estrogen receptor α (ESR1) polymorphisms and cognitive decline was investigated. METHODS: Chinese older adults (n = 284) were recruited, and the cognitive profile was follow-up over 2-year period. Twenty ESR1 polymorphisms were investigated and correlated with the cognitive decline for the subjects. RESULTS: Significant association was found between ESR1 polymorphisms (rs9340799 [ESR1+351], rs1801132 [ESR1+975], rs6557171, rs9397456, and rs1884049) and subjects with no dementia (Clinical Dementia Rating, CDR 0) and very mild dementia (CDR 0.5). Several ESR1 polymorphisms were associated with cognitive decline as assessed by Chinese versions of Mini-Mental State Examination and Alzheimer Disease Association Scales-Cognitive Subscale. Different sets of ESR1 polymorphisms were associated with cognitive decline from CDR 0 to 0.5 and CDR 0.5 to 1. ESR1 polymorphisms (rs3853248, rs22334693 [ESR1+397], rs9340799 [ESR1+351], rs9397456, rs1801132 [ESR1+975], rs2179922, rs932477, and rs9341016) were associated with the deterioration of episodic memory among subjects with baseline CDR 0, indicating these polymorphisms might be markers for episodic memory decline at an earlier stage. CONCLUSION: This study showed association between ESR polymorphisms and cognitive decline or specific areas in cognitive profile. These findings might be useful in identifying individuals at risk for early intervention, and more research is required to elucidate the underlying mechanisms.

Alzheimer's disease-related loss of Pin1 function influences the intracellular localization and the processing of AßPP.

Increased amyloidogenic processing of the amyloid-ß protein precursor (AßPP) is a characteristic of Alzheimer's disease (AD). We previously observed that the prolyl isomerase Pin1, which is down-regulated in AD, regulates AßPP conformation accelerating cis/trans isomerization of the phospho-Thr668-Pro669 peptide bond, and that Pin1 knockout in mice increases the amyloidogenic processing of AßPP, although the underlying mechanism is still unknown. Since the intracellular localization of AßPP determines whether the processing will be amyloidogenic or non-amyloidogenic, here we addressed the question whether loss of Pin1 function affects the intracellular localization of AßPP, influencing AßPP processing. Using cellular models of Pin1 knockout and Pin1 knockdown, we have demonstrated that lowering Pin1 levels changed the intracellular localization and the processing of AßPP. Under these conditions, less AßPP was retained at the plasma membrane favoring the amyloidogenic processing, and the kinetics of AßPP internalization increased as well as the nuclear trafficking of AßPP C-terminal fragment AICD. In addition, AßPPThr668Ala mutant, which cannot bind to Pin1 and retains more trans conformation, rescued the levels of AßPP at the plasma membrane in Pin1 knockout cells. Thus, loss of Pin1 function contributes to amyloidogenic pathways, by facilitating both the removal of AßPP from compartments where it is mostly non-amyloidogenic and its internalization to more amyloidogenic compartments. These data suggest that physiological levels of Pin1 are important to control the intracellular localization and metabolic fate of Thr668-phosphorylated AßPP, and regulation of AßPP conformation is especially important in pathologic conditions of AßPP hyperphosphorylation and/or loss of Pin1 function, associated with AD.

Association between tumor necrosis factor-alpha promoter polymorphism and Alzheimer's disease.

Tumor necrosis factor-alpha (TNFalpha) gene polymorphisms have been reported to be associated with Alzheimer's disease (AD) in Caucasian populations. Three TNFalpha polymorphisms (-857, -863, and -1,031) were studied in a Chinese population. A high-risk TNFalpha haplotype (-1,031C-863C-857C) with an odds ratio of 2.54 (95% CI 1.37 to 4.79) for AD was identified. No interaction effect of APOE and TNFalpha genotypes was found, but both acted as important risk factors for AD.