GeneLink: a database to facilitate genetic studies of complex traits

Abstract

Background: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database.

Results: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers.

Conclusions: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at http://research.nhgri.nih.gov/genelink.

Figure 1

Main menu GeneLink's main menu available following login. GeneLink is a platform-independent, Web-accessible database. Access to GeneLink is password-protected. Here the user (lgilland) has been given import, export, view, and admin, permissions.

Figure 2

Relational design Relational design of GeneLink's 11 primary tables. Primary keys are indicated in red and foreign keys in blue. GeneLink enables pedigree information stored in the Families and Pedigrees tables to be easily merged with genotypic data stored in the Genotypes table. In the Pedigrees, Liability Classes, Trait Score, and Trait Translation tables GeneLink also manages extensive phenotypic data. The Markers and Primer tables store information regarding polymorphisms being genotyped and the Maps table stores genetic or physical map information, which determines the order in which data is exported. GeneLink's Primer and DNA tables provide labs with an easily implemented inventory system.

Figure 3

Allele translation The Allele Translations table provides a key linking the "translated" allele (Translation) to the original size in base-pairs score (Allele). All LINKAGE or RelCheck exports will use identical "allele translation codes." In this example, 15 alleles have been identified for marker D1S206. New alleles identified after the first export (in this example alleles 10 to 15) will be added to the end of a marker's allele translation ensuring consistent recoding of alleles across families.

Figure 4

Liability classes Within GeneLink liability classes can be defined using any combination of age, sex, and affection status.

Figure 5

Export by chromosome The Export Genotype Data screen prompts users to specify 1) which chromosome to export, 2) which trait(s) to export (Status Field), 3) how to define liability classes, 4) what file format is desired and 5) which families to include in the export.

Figure 6

Export report GeneLink's Export Report provides a summary of all pertinent information relating to an export. This includes the file name (which incorporates the project ID, chromosome exported, user ID, and a random number), date the file was created and by whom. The Export Report also records which chromosome, phenotypes (status field) and families, were exported and in what file format. Finally, the Export Report also provides the distance between markers being exported.

Figure 7

A, and B. Import process Outline of Import process illustrates GeneLink's ability to be used in laboratories that include duplicated samples and double scoring for quality control purposes. Import process includes within table duplicate check and across table differences check. Using the Single table import allows the differences step to be skipped.

Figure 8

A, B, and C. Example of import (A), duplicates (B), and differences (C) reports Import report stores all information regarding genotypes imported into GeneLink. This information includes number of records imported (how many unique individuals, how many markers) as well as the name of the file in which records are stored. The duplicates process checks for duplicate genotypes within a table. A duplicate is defined as records with the same FamInd ID and marker. All duplicate records are reported. If duplicate records have the same two alleles then one record is deleted. If the two duplicate records do not have matching alleles than the user is prompted to select which record to delete. The differences process looks for differences in genotypes compared across tables (independently scored by two researchers). All differences are reported and the user is prompted to resolve each appropriately. The user is given the option to save either record or if either score isn't acceptable then new genotype can be indicated.

Figure 9

Status report GeneLink's status reports allow collaborators to easily tract the project's progress by site. Reports show markers by chromosome (in map order) and the status of each marker for each site. By site, markers can be Not started, In Lab, Genotypes Imported, Single Table Imported, Waiting for Comparison, Compared and Ready, Ready to Finalize and Ready to Export. Data can be exported only after all markers on a given chromosome for a given site are Ready to Export. In this example we are looking at markers D21S1256, D21S1914, D21S1909, D21S1252, D21S2055, D21S266, and D21S1446 on chromosome 21 for sites JHU, AAHPC, AAHPC2, Sweden, Finland and Michigan. Here data is ready to export for family sites AAHPC2 and Sweden.

Figure 10

A, and B. Marker (A) and individual (B) summaries GeneLink's Marker Summary provides success rates and heterozygosity for individual markers typed in the study. The Marker Summary also provides information regarding when the genotype records for this marker were imported (Import Dates). Marker quality can also be evaluated using the Flags column. Genotypes can be flagged with a T to temporarily blank scores from analyses. This is used for un-resolvable Mendelian inconsistencies. The R flag can be used for replaced DNA samples until the new DNA sample is evaluated. Neither T nor R flagged genotypes are exported. Individual summaries also provide global quality assurance information such as success or flag rates.