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Integrating databases

• Population genetics
• Phenotype, genotype, and function
• References

Population genetics

GnomAD (version r2.0.2) (Lek et al., 2016) was used in these studies as the best source of population genetics data. The reference genome is GRCh37. Offline local database mirrors were used in most cases. Input sets used GnomAD variant allele frequencies and reference sequences processed as VCF and CSV files. outlines a specific data transformation using the gnomAD database, but in general, gnomAD was used as a filtering threshold for determining the expected population frequency of each variant. A strict threshold for rare variants could be set to ignore and candidate variants that are more frequent than 0.001. However, in most cases a more lenient level is used and any remaining benign or common variants are removed by “technical control” (filter on cohort to remove common variants between individuals that do not share a phenotype). A more modest cut-off threshold allows us to sometimes identify variant that are present in the general population, which are responsible for a recessive disease with no predictable heterozygous loss-of-function intolerance.

Other sources of population genetics data comes from resources such as CliVar and dbSNP, which as they grow in size become an annotated and curated for of population data. These resources allow us to calculate the expected frequencies for disease-causing variants. However, since these are manually curated database and predominantly European based, they are inherently biased and not reliable for statistical applications.

Phenotype, genotype, and function

Population genetics database gnomAD has been individually addressed in section [subsec:gnomad], as this is the most important type of annotation and filtering criteria for genetic determinants of rare disease. Additionally, in these studies many phenotype and genotype databases have been used for annotation and interpretation. Specifically, the most frequently used data came from MGI Phenotype, MorbidMap, VOC MammalianPhenotype, Gencode symbol, UniProtKB, Enterez ID, ENSGene ID, GO ID, Description, OMIM, BIOGRID interactions, HGMD human phenotype, ClinVar, and dbSNP. In most cases, every candidate variant was annotated with the main information per gene from a local database containing the information from each of the listed resources.

These are the “basic” information databases that we used to annotate variants. In a cohort study, data mining can find correlations and was therefore included for posterity as it does not significantly increase the data storage. Even if an obvious cause of disease was found we may later return to the data to find other cofactors or genetic modifiers. Or for example, in a single case study, a variant of unknown significance may have no statistical basis to be selected or ignored. We use this information to decide if that mutation is worth consideration: Is it in a protein domain of known function? Are there other cases reported with the same phenotype? What is the gene function, ontology, etc.?

We have also used some gene lists that are specific to disease, druggability, etc. A major contributor for collecting these gene lists has been the Mac Arthur et al. (Lab, 2018). These gene lists can be used is special cases. For example, a study looking at (1) dominant pathogenic mutations, and (2) in known immune genes might filter to included only those known observables. We could decide to only study SNPs in FDA-approved drug targets.

(Verma et al., 2018) take an interesting approach to comparing druggable targets with population genetics data. DrugBank is a database for over 800 genes with over 950 unique drugs. Genetic data can be filtered for these genes and targeted for LoF variants. Association analysis consists of logistic regression using the ICD-9 codes, and linear regression using quantitative variables. This gene binding and regression analysis steps are done using BioBin.

The International Statistical Classification of Diseases and Related Health Problems (commonly known as the ICD) provides alpha-numeric codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. Nearly every health condition can be assigned to a unique category and given a code, up to six characters long. Such categories usually include a set of similar diseases

BioBin relies on the Library of Knowledge Integration (LOKI), which integrates multiple databases providing a comprehensive biological knowledge platform for variant binning (Pendergrass et al., 2013). The LOKI database consolidates biological information from several sources, most notably the National Center for Biotechnology (NCBI) dbSNP and Entrez Gene, Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, Gene Ontology (GO), Protein families database (Pfam), NetPath-signal transduction pathways, amongst others (missing reference).

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