Identification of Novel Alzheimer\u2019s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

Dmitry Prokopenko,Rudolph E Tanzi,Lars Bertram,Dawn L Demeo,Nan Laird,Winston Hide,Julian Hecker,Brad A Chapman,Kristina Mullin,Christoph Lange,Rory Kirchner,Oliver Hoffman

doi:10.1038/s41598-020-61883-6

Abstract

With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer’s Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (Pinter = 1.83 × 10−7), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a substantial burden for patients, but their families, society and the healthcare system
family-based association tests (FBATs) have been recognized to be robust to population structure and to have the advantage of flexible model building based on solely Mendelian transmissions[22]
We found that variants in GRID1 and RIOK3 are located in repeat regions within retrotransposons

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a substantial burden for patients, but their families, society and the healthcare system. Large-scale meta-analyses of genotyped data have largely focused on the AD affection status itself, rather than on sex-specific AD effects[19,20,21] This may be attributed to the fact that understanding and modelling gene-by-environment interactions still remain major challenges in the field, due to lack of power given current analytic methods. FBATs have been recognized to be robust to population structure and to have the advantage of flexible model building based on solely Mendelian transmissions[22] This feature of FBATs becomes important when statistical inference is made for an environment interaction effect in the context of WGS-based data, where most of the variants are rare. In the context of sex-specific analyses, this issue is further aggravated as many genetic regions show sequence homology with the X-chromosome[29] This can lead to differential genotyping error rates for females and males due to different X chromosome dosage. Ignoring the impact of such sex-specific genotyping/sequencing errors can lead to substantially inflated type-1 errors[29]

Methods

Results

Conclusion