A non-threshold region-specific method for detecting rare variants in complex diseases

Abstract

A region-specific method, NTR (non-threshold rare) variant detection method, was developed—it does not use the threshold for defining rare variants and accounts for directions of effects. NTR also considers linkage disequilibrium within the region and accommodates common and rare variants simultaneously. NTR weighs variants according to minor allele frequency and odds ratio to combine the effects of common and rare variants on disease occurrence into a single score and provides a test statistic to assess the significance of the score. In the simulations, under different effect sizes, the power of NTR increased as the effect size increased, and the type I error of our method was controlled well. Moreover, NTR was compared with several other existing methods, including the combined multivariate and collapsing method (CMC), weighted sum statistic method (WSS), sequence kernel association test (SKAT), and its modification, SKAT-O. NTR yields comparable or better power in simulations, especially when the effects of linkage disequilibrium between variants were at least moderate. In an analysis of diabetic nephropathy data, NTR detected more confirmed disease-related genes than the other aforementioned methods. NTR can thus be used as a complementary tool to help in dissecting the etiology of complex diseases.

Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

“…Over the past decades, various studies have identified a role for common genetic variation on cytokine level and response, however a significant proportion of inter-individual variability remains to be determined [12][13][14][15]. Considering the increasing evidence that specific combinations of variants with variable frequencies can influence phenotypic variability [16][17][18], in particular for a combination of phenotypic characteristics that do not fit one specific clinical diagnosis [30], we hypothesized that the inter-individual variability in cytokine responses might be subjectable to same concept. For this purpose, we sequenced the coding regions of 48 genes related to the IL-1 pathway in almost 500 healthy individuals, and assessed IL-1ß and IL-6 levels in whole blood in response to in vitro LPS, PHA, C. albicans and S. aureus.…”

“…With recent advancements in sequencing technologies, the ability to study the role of rare and low-frequency variants has remarkably improved, and its value has been proven in several studies. For instance, increasing evidence is showing that the combined effect of common-and rare variants could partially explain the missing heritability problem in complex diseases [16][17][18]. The relatively smallto-moderate effects of common variants can be significantly modified by the presence or absence of (multiple) rare variants [19], and thus could partially explain the 'missing heritability' in the interindividual variability in immune responses.…”

Exautomate: A user-friendly tool for region-based rare variant association analysis (RVAA)

“…One method frequently used for region-based RVAA is the sequence kernel association test (SKAT) [15][16][17][18] . While the method has been useful in revealing rare variants and genomic loci of interest in complex traits and diseases-such as cardiovascular disease, body-mass index, height, and neurodegenerative diseases [19][20][21][22] -reproducing these results can be difficult.…”