From Single-SNP to Wide-Locus: Genome-Wide Association Studies Identifying Functionally Related Genes and Intragenic Regions in Small Sample Studies

Wittkowski, Knut M.; Sonakya, V.; Song, Tingting; Seybold, Martin P.; Keddache, Mehdi; Durner, Martina

doi:10.2217/pgs.13.28

Cited by 8 publications

(24 citation statements)

References 47 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With u -statistics for genetically structured wide-locus data comprising several neighboring SNPs (μGWAS) addressing the former two conditions, we have recently confirmed axonal guidance and Ca 2+ signaling as key pathways in childhood absence epilepsy (CAE) 20 from 185 cases and publicly available controls only. As shared genetic risk factors have been suggested for neurodevelopmental disorders, in general, 21 and epilepsies and ASD, in particular, 22, 23, 24 we hypothesized that these pathways are involved in ASD as well.…”

Section: Introductionmentioning

confidence: 96%

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism

Sonakya

Bigio

et al. 2014

Transl Psychiatry

View full text Add to dashboard Cite

The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non-randomized) genome-wide association studies (GWAS), a correlation between P-values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for ‘genome-wide significance'. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9–24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade.

show abstract

Section: Introductionmentioning

confidence: 96%

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism

Sonakya

Bigio

et al. 2014

Transl Psychiatry

View full text Add to dashboard Cite

show abstract

“…• In epilepsy, (Wittkowski 2013) muGWAS confirmed the Ras pathway and known drug targets (ion channels, IL1B). In that analysis, muGWAS was also compared with a parametric analogue, logistic regression with interaction terms for neighboring SNPs (lrGWAS).…”

Section: Validationmentioning

confidence: 86%

“…In this analysis, conventional single-SNP GWAS (ssGWAS) are complemented with a computational biostatistics approach (muGWAS, GWAS using muStat (Wittkowski 2012) ) that incorporates knowledge about genetics into the method (Wittkowski 2010, Sections 4.3.4 and 4.4.2;Wittkowski 2013) and knowledge about the nature of GWAS into the decision strategy. (Wittkowski 2014) Statistical methods tend to have higher power if they are based on more realistic assumptions, which, in biology, tend to be weak.…”

Section: Methodsmentioning

confidence: 99%

“…(Mann 1947;Wilcoxon 1954;Kruskal 1957) The same data was then analyzed using a u-test for genetically structured multivariate data. (Wittkowski 2013) U-statistics avoid model-misspecification biases by replacing linear/logistic (Wu 2010b) with non-parametric kernels. (Li 2012) Below, we describe the assumptions about genetics and GWAS that are implemented in the statistical method and decision strategy and refer to published empirical validation of this approach.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer

Wittkowski

Dadurian

Seybold

et al. 2017

Preprint

View full text Add to dashboard Cite

Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids via alphacyclodextrins (αCD) as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of β1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (βCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller αCDs also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPβCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with βCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted in women with triplenegative breast cancer, who progress fast and have few treatment options.peer-reviewed)

show abstract

“…The methods used for human GWAS are particularly ill-suited to feature selection in RNA viruses, due to the short genome length, very high substitution rate and diversity, and the high degree of genetic linkage [48,49]. Human GWAS tend to concentrate on common variants to explain the observed phenotypes [15,49,50] by looking at individual SNPs, thus having severe limitations in the presence of epistasis [15,48,50,51]; our work demonstrates that non-parametric machine-learning based methods -such as RFA -are more appropriate in the context of RNA viruses, by identifying sets of substitutions associated with a particular phenotypic class, rather than solely evaluating the significance of individual polymorphisms [48,51]. The incorporation of interactions among predictor variables in RFA makes it possible to identify possible epistatic effects, as highlighted in Figure 3, with substitutions being determinant for host discrimination when found together with other substitutions at other sites, but being fairly unimportant by themselves.…”

Section: Discussionmentioning

confidence: 99%

Feature Selection Methods for Identifying Genetic Determinants of Host Species in RNA Viruses

Águas

Ferguson

2013

PLoS Comput Biol

View full text Add to dashboard Cite

Despite environmental, social and ecological dependencies, emergence of zoonotic viruses in human populations is clearly also affected by genetic factors which determine cross-species transmission potential. RNA viruses pose an interesting case study given their mutation rates are orders of magnitude higher than any other pathogen – as reflected by the recent emergence of SARS and Influenza for example. Here, we show how feature selection techniques can be used to reliably classify viral sequences by host species, and to identify the crucial minority of host-specific sites in pathogen genomic data. The variability in alleles at those sites can be translated into prediction probabilities that a particular pathogen isolate is adapted to a given host. We illustrate the power of these methods by: 1) identifying the sites explaining SARS coronavirus differences between human, bat and palm civet samples; 2) showing how cross species jumps of rabies virus among bat populations can be readily identified; and 3) de novo identification of likely functional influenza host discriminant markers.

show abstract

From Single-SNP to Wide-Locus: Genome-Wide Association Studies Identifying Functionally Related Genes and Intragenic Regions in Small Sample Studies

Cited by 8 publications

References 47 publications

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism

Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer

Feature Selection Methods for Identifying Genetic Determinants of Host Species in RNA Viruses

Contact Info

Product

Resources

About