Role of ABCA7 loss-of-function variant in Alzheimer\u27s disease: A replication study in European–Americans

INTRODUCTION: A recent study found a significant increase of ABCA7 loss-of-function variants in Alzheimer’s disease (AD) cases compared to controls. Some variants were located on noncoding regions, but it was demonstrated that they affect splicing. Here, we try to replicate the association between AD risk and ABCA7 loss-of-function variants at both the single-variant and gene level in a large and well-characterized European American dataset. METHODS: We genotyped the GWAS common variant and four rare variants previously reported for ABCA7 in 3476 European–Americans. RESULTS: We were not able to replicate the association at the single-variant level, likely due to a lower effect size on the European American population which led to limited statistical power. However, we did replicate the association at the gene level; we found a significant enrichment of ABCA7 loss-of-function variants in AD cases compared to controls (P = 0.0388; odds ratio =1.54). We also confirmed that the association of the loss-of-function variants is independent of the previously reported genome-wide association study signal. CONCLUSIONS: Although the effect size for the association of ABCA7 loss-of-function variants with AD risk is lower in our study (odds ratio = 1.54) compared to the original report (odds ratio = 2.2), the replication of the findings of the original report provides a stronger foundation for future functional applications. The data indicate that different independent signals that modify risk for complex traits may exist on the same locus. Additionally, our results suggest that replication of rare-variant studies should be performed at the gene level rather than focusing on a single variant

Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.

Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations

List of reported^* pathogenic variants in genes for Alzheimer disease (AD), Frontotemporal dementia (FTD) and Parkinson disease (PD) detected in the familial cohort, the sporadic KANL cohort and the ADSP sporadic cohort.

<p>We provide the number and percentage of families (NF), cases (CA) and controls (CO) that were carriers of each variant.</p

Burden test for KANL and ADSP unrelated datasets.

<p>Collapsing and combine (CMC) test of rare variants by Fisher's exact test for (i) variants with a MAF≤1% and categorized to have a high or moderated effect (MAF≤1% HM) and (ii) singleton variants categorized to have a high or moderated effect (AC1 HM), for the unrelated datasets analyzed in this study (unrelated KANL and Sporadic ADSP). Number of polymorphic variants (N), odds ratio (OR) and two sided pvalue (<i>P</i>) are given. Enriched genes with nominally significant pvalues are bold highlighted.</p

Demographic data for the cohorts employed in this study and analysis plan.

<p>Demographic data for the cohorts employed in this study and analysis plan.</p

Segregation pattern of reported pathogenic mutations detected in the familial cohort (452 families).

<p>The number of carriers and non-carriers in both affected and cognitively normal family members is displayed, along with the average AAO for cases and average ALA for controls. The first reference for each variant is also provided.</p

Pedigree structure of families' carriers of genetic variants.

<p>(a) <i>PSEN1</i> p.(Ala79Val), (b) <i>PSEN2</i> p.(Met174Val), (c) <i>GRN</i> p.(Arg110*). Age at onset (AAO), age at last assessement (ALA) and APOE status is provided for each genotyped individual.</p