Recent Consanguinity and Outbred Autozygosity Are Associated With Increased Risk of Late-Onset Alzheimer’s Disease
Bibliographic record
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 (F ROH ) and the number (N ROH ) 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".