Statistical approaches to the analysis of whole-genome sequencing in autosomal-dominant macular dystrophy

Abstract

Purpose : The importance of linkage analysis has again been brought to the fore after years of taking a backseat during the era of GWAS partly due to the marked reduction in the sequencing cost. In this study, we tested the application of several family-based methods to detect the causal gene in a Greek family with autosomal dominant macular dystrophy. The inherited macular dystrophies encompass a heterogeneous group of disorders that affect the specialized central region of the retina responsible for central visual acuity leading to vision loss. It has several patterns of inheritance.

Methods : We studied a large six-generation family from Greece in which 14 members had the disease (MCDR5). Whole genome sequencing was done in 9 individuals in the family. Rigorous quality control steps using PLINK and Sib-pair were done. The data was annotated with the Rutgers Linkage Map to create a genetic map position for each marker. We then employed several methods for the analysis of family data, parametric linkage analysis using the software MERLIN and SEQlinkage, family-based association methods appropriate for rare variants implemented in FBAT and FFBSKAT.

Results : We genotyped 6 diseased and 3 non-diseased members of a Greek family in the age range 14 to 88 years. All affected members exhibited features of the disease such as decreased central vision in the second decade of life and macular abnormalities in the posterior pole of the retina. Some 17015644 variants were called and 13471103 passed initial quality control. Of these, 124837 were coding variants, primarily 76307 non-synonymous and 40419 synonymous variants. Linkage and association analyses are ongoing and will be presented.

Conclusions : Family-based study designs are re-emerging as a powerful tool to potentially identify the causative genes in many diseases. Compared to studies of unrelated individuals, family studies have the advantage of having lower sample size requirements for sufficient power to detect rare variants of moderate to large effect. Here, we harnessed the power of family-based designs to detect susceptibility genes in a family who had already been screened for known gene mutations but had not had a causal mutation identified. Determination of a locus in this study will help give us a better understanding of this blinding disease leading to novel therapeutic approaches in macular dystrophy.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.