Meffil: efficient normalization and analysis of very large DNA methylation datasets.

Motivation: DNA methylation datasets are growing ever larger both in sample size and genome coverage. Novel computational solutions are required to efficiently handle these data. Results: We have developed meffil, an R package designed for efficient quality control, normalization and epigenome-wide association studies of large samples of Illumina Methylation BeadChip microarrays. A complete re-implementation of functional normalization minimizes computational memory without increasing running time. Incorporating fixed and random effects within functional normalization, and automated estimation of functional normalization parameters reduces technical variation in DNA methylation levels, thus reducing false positive rates and improving power. Support for normalization of datasets distributed across physically different locations without needing to share biologically-based individual-level data means that meffil can be used to reduce heterogeneity in meta-analyses of epigenome-wide association studies. Availability and implementation: https://github.com/perishky/meffil/. Supplementary information: Supplementary data are available at Bioinformatics online.

Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia.

Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ~1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10(-4)), excitability (P=9.0 × 10(-4)) and cell adhesion and trans-synaptic signaling (P=2.4 × 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.

Association of matrilin-3 polymorphisms with spinal disc degeneration and osteoarthritis of the first carpometacarpal joint of the hand.

BACKGROUND: Seven polymorphisms in the matrilin-3(MATN3) gene were previously tested for genetic association with hand osteoarthritis in an Icelandic cohort. One of the variants, involving a conserved amino acid substitution (T303M; SNP5), was related to idiopathic hand osteoarthritis. OBJECTIVES: To investigate SNP5 and two other promising polymorphisms (rs2242190; SNP3, rs8176070; SNP6) for association with radiographic and symptomatic hand osteoarthritis phenotypes, as well as other heritable phenotypes. METHODS: Polymorphisms were examined in two distinct cohorts of subjects: a population based sample from the Rotterdam study (n = 809), and affected siblings from the genetics, osteoarthrosis and progression (GARP) study (n = 382). RESULTS: The originally described association of T303M with the hand osteoarthritis phenotype was not observed in the populations studied. In the Rotterdam sample, however, carrying the T allele of T303M conferred an odds ratio of 2.9 (95% confidence interval (CI), 1.2 to 7.3; p = 0.02) for spinal disc degeneration. In the GARP study, carriers of the A allele of SNP6 had an odds ratio of 2.0 (95% CI, 1.3 to 3.1, p = 0.004) for osteoarthritis of the first carpometacarpal joint (CMC1) as compared with the Rotterdam sample as a control group. Subsequent haplotype analysis showed that a common haplotype, containing the risk allele of SNP6, conferred a significant risk in sibling pairs with CMC1 osteoarthritis (odds ratio = 1.7 (95% CI, 1.1 to 2.7, p = 0.02)). CONCLUSIONS: These associations suggest that the MATN3 region also determines susceptibility to spinal disc degeneration and CMC1 osteoarthritis.

Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites.

OBJECTIVE: To confirm the association of 2 variants of the Frizzled-related protein gene (FRZB) with osteoarthritis (OA) of the hip, and to investigate whether these variants also associate with other heritable generalized OA phenotypes. METHODS: An association analysis of 2 variants (R200W and R324G) of FRZB was performed in a random sample of 1,369 subjects (ages 55-70 years) from a population-based cohort (the Rotterdam Study) scored for radiographic characteristics of OA in the hip, hand, spine, and knee and in a patient population of Caucasian probands (ages 40-70 years) and their siblings selected for the presence of primary symptomatic OA at multiple sites. RESULTS: The allele frequency of the 2 variants was not significantly different between subjects with hip radiographic OA (ROA) and controls. The frequency of the G allele of the R324G variant was significantly increased in subjects with generalized ROA from the Rotterdam Study (0.10) and in subjects from the Genetics, osteoARthritis and Progression study (0.11) compared with that in controls from the Rotterdam Study (0.08). Carriers of this G allele had increased susceptibility for generalized ROA (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 0.9-1.9, P = 0.10) or familial symptomatic OA at multiple sites (OR 1.6, 95% CI 1.1-2.3, P = 0.02). CONCLUSION: Our results confirm that the R324G variant of the FRZB gene is involved in OA and indicate a role of this variant in several generalized OA phenotypes. A more extended OA phenotype may indeed be expected from genetic variation in an essential pathway of skeletal development such as Wnt signaling.