The complete linkage disequilibrium test: a test that points to causative mutations underlying quantitative traits

Area of Science:

• Genetics
• Statistical Genetics
• Genomic Analysis

Background:

• Distinguishing causative single nucleotide polymorphisms (SNPs) from those in complete linkage disequilibrium (LD) is a genetic challenge.
• The Complete Linkage Disequilibrium (CLD) test is introduced to assess if a SNP is in complete LD with a causative mutation.

Purpose of the Study:

• To evaluate the performance of the CLD test in simulated datasets.
• To determine the power and accuracy of the CLD test in identifying causative SNPs.

Main Methods:

• The CLD test involves an association analysis followed by evaluating differences in log-likelihood ratios between the top two markers.
• Significance thresholds were established using data excluding the causative SNP to control type-I error rates.

Main Results:

• Analysis I detected quantitative trait loci (QTLs) in 99.4% of simulations when the causative SNP explained 48% of variance.
• The CLD test confirmed causative SNPs in 28% of simulations (280 out of 1000) with 48% QTL variance.
• Test power decreased to 23% with doubled error variance and 16% when using sequence data, though confirmed SNPs were correctly positioned.

Conclusions:

• The CLD test can provide evidence for causative SNPs but may have limited power when markers are closely linked.
• Functional evidence is recommended alongside CLD test results for definitive causative SNP identification in complex genetic scenarios.