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. 2021 Jan 29:11:629373.
doi: 10.3389/fgene.2020.629373. eCollection 2020.

Recent Consanguinity and Outbred Autozygosity Are Associated With Increased Risk of Late-Onset Alzheimer's Disease

Valerio Napolioni  1 , Marzia A Scelsi  2 , Raiyan R Khan  3 , Andre Altmann  2 , Michael D Greicius  4
Affiliations

Recent Consanguinity and Outbred Autozygosity Are Associated With Increased Risk of Late-Onset Alzheimer's Disease

Valerio Napolioni et al. Front Genet. .

Abstract

Prior work in late-onset Alzheimer's disease (LOAD) has resulted in discrepant findings as to whether recent consanguinity and outbred autozygosity are associated with LOAD risk. In the current study, we tested the association between consanguinity and outbred autozygosity with LOAD in the largest such analysis to date, in which 20 LOAD GWAS datasets were retrieved through public databases. Our analyses were restricted to eight distinct ethnic groups: African-Caribbean, Ashkenazi-Jewish European, European-Caribbean, French-Canadian, Finnish European, North-Western European, South-Eastern European, and Yoruba African for a total of 21,492 unrelated subjects (11,196 LOAD and 10,296 controls). Recent consanguinity determination was performed using FSuite v1.0.3, according to subjects' ancestral background. The level of autozygosity in the outbred population was assessed by calculating inbreeding estimates based on the proportion (FROH) and the number (NROH) of runs of homozygosity (ROHs). We analyzed all eight ethnic groups using a fixed-effect meta-analysis, which showed a significant association of recent consanguinity with LOAD (N = 21,481; OR = 1.262, P = 3.6 × 10-4), independently of APOE ∗4 (N = 21,468, OR = 1.237, P = 0.002), and years of education (N = 9,257; OR = 1.274, P = 0.020). Autozygosity in the outbred population was also associated with an increased risk of LOAD, both for F ROH (N = 20,237; OR = 1.204, P = 0.030) and N ROH metrics (N = 20,237; OR = 1.019, P = 0.006), independently of APOE ∗4 [(F ROH, N = 20,225; OR = 1.222, P = 0.029) (N ROH, N = 20,225; OR = 1.019, P = 0.007)]. By leveraging the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data, we determined that LOAD subjects do not show an enrichment of rare, risk-enhancing minor homozygote variants compared to the control population. A two-stage recessive GWAS using ADSP data from 201 consanguineous subjects in the discovery phase followed by validation in 10,469 subjects led to the identification of RPH3AL p.A303V (rs117190076) as a rare minor homozygote variant increasing the risk of LOAD [discovery: Genotype Relative Risk (GRR) = 46, P = 2.16 × 10-6; validation: GRR = 1.9, P = 8.0 × 10-4]. These results confirm that recent consanguinity and autozygosity in the outbred population increase risk for LOAD. Subsequent work, with increased samples sizes of consanguineous subjects, should accelerate the discovery of non-additive genetic effects in LOAD.

Keywords: Alzheimer disease; autozygosity; directional dominance; ethnic differences; inbreeding; recessive inheritance; runs of homozygosity (ROH); uniparental isodisomy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow-chart of the workflow adopted in the data QC/harmonization/ancestry-determination processing of the full dataset.
FIGURE 2
FIGURE 2
Analysis of the genetic structure confirmed the effectiveness of our ancestry-determination pipeline. Ancestry proportions of the 21,492 unrelated subjects studied (from the eight determined ethnic groups) as revealed by the ADMIXTURE software (Alexander et al., 2009), using pruned (MAF ≥ 0.01, r2 ≤ 0.1) SNPs at K = 6. Each color represents a different ancestral component, and each ancestry is a mixture of different components. ACD, African–Caribbean from Dominican Republic; AJE, Ashkenazi-Jewish Europeans; ECD, European–Caribbean from Dominican Republic; FCN, French–Canadians; FIN, Finnish Europeans; NWE, North-Western Europeans; SEE, South-Eastern Europeans; YRI, African Yoruba.
FIGURE 3
FIGURE 3
The eight ethnic groups analyzed showed ethnic-specific differences in Alzheimer’s-relevant risk factors. (A) mean age, (B) EDU, (C) APOE∗2 frequency, (D) APOE∗4 frequency, (E) inbreeding coefficient, and (F) number of ROHs (>1 Mb) differ significantly across the eight ethnic groups analyzed (P < 0.00001).
FIGURE 4
FIGURE 4
Numerous cases of putative isodisomy misidentified as consanguineous subjects. Fifty-six subjects identified as consanguineous by FSuite v1.0.3 (Gazal et al., 2014) showed a single homozygous region over 10 Mb on just one chromosome, the homozygosity cut-off previously reported to define the presence of putative uniparental isodisomy (UPD). Two female subjects showing a putative UPD on X-chromosome are not shown. Red = LOAD; Blue = Control.
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