Evaluating Power and Type 1 Error in Large Pedigree Analyses of Binary Traits

Abstract

Studying population isolates with large, complex pedigrees has many advantages for discovering genetic susceptibility loci; however, statistical analyses can be computationally challenging. Allelic association tests need to be corrected for relatedness among study participants, and linkage analyses require subdividing and simplifying the pedigree structures. We have extended GenomeSIMLA to simulate SNP data in complex pedigree structures based on an Amish pedigree to generate the same structure and distribution of sampled individuals. We evaluated type 1 error rates when no disease SNP was simulated and power when disease SNPs with recessive, additive, and dominant modes of inheritance and odds ratios of 1.1, 1.5, 2.0, and 5.0 were simulated. We generated subpedigrees with a maximum bit-size of 24 using PedCut and performed two-point and multipoint linkage using Merlin. We also ran MQLS on the subpedigrees and unified pedigree. We saw no inflation of type 1 error when running MQLS on either the whole pedigrees or the sub-pedigrees, and we saw low type 1 error for two-point and multipoint linkage. Power was reduced when running MQLS on the subpedigrees versus the whole pedigree, and power was low for two-point and multipoint linkage analyses of the subpedigrees. These data suggest that MQLS has appropriate type 1 error rates in our Amish pedigree structure, and while type 1 error does not seem to be affected when dividing the pedigree prior to linkage analysis, power to detect linkage is diminished when the pedigree is divided.

Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment

“…The pedigree, which explained the known relationships between the founder brothers and the Robinson Crusoe validation cohort, included 288 individuals (321 bits, where a bit is defined as twice the number of non-founders—the number of founders) and so had to be broken into smaller sets for linkage analyses. This segmentation process discards information and can reduce the power to detect linkage if individuals sharing the linked chromosome segment are split between sub-pedigrees [ 56 ]. Lastly, since we hypothesize that SLI in this population has a complex genetic basis and involves incomplete and a high phenocopy frequency, it is possible that the power to detect linkage is insufficient.…”

Examination of Candidate Exonic Variants for Association to Alzheimer Disease in the Amish

“…Additionally, this method allows for the inclusion of samples with unknown or unclear affection status, increasing the overall sample size. Type 1 error rates for the method are not inflated when used for the Amish [ 29 ]. This association test was used for both stages of the study, analysis of sequence variants and follow-up genotyping.…”

“…By genotyping the prioritized variants in over 1,100 samples, the power limitations of the screening population may be overcome and associations may be detected. Previous studies in this Amish population investigated this software’s power to detect associations [ 29 ]. For dominant and additive models, there was greater than 90% power to detect an association at p < 0.05 when the simulated odds ratio (OR) was at least 2 and the minor allele frequency was held constant at 0.2.…”

Linkage of familial essential tremor to chromosome 5q35

“…Essential tremor (ET) is a movement disorder characterized by bilateral postural tremor, typically in the upper limbs, and sometimes comorbid with other movement disorders such as PD and dystonia. ET is believed to be a central nervous disorder arising from an oscillating source in the brain …”

“…ET is believed to be a central nervous disorder arising from an oscillating source in the brain. 2 ET is one of the most common movement disorders in adults and occurs in all ethnic groups. Overall, the prevalence of ET in the general population is 0.9% 3 ; however, prevalence increases with age.…”