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. 2021 Feb 24;11(1):142.
doi: 10.1038/s41398-020-01145-1.

Long runs of homozygosity are associated with Alzheimer's disease

Sonia Moreno-Grau  1   2 , Maria Victoria Fernández  3   4 , Itziar de Rojas  1   2 , Pablo Garcia-González  1 , Isabel Hernández  1 , Fabiana Farias  3   4 , John P Budde  3   4 , Inés Quintela  5 , Laura Madrid  6 , Antonio González-Pérez  6 , Laura Montrreal  1 , Emilio Alarcón-Martín  1 , Montserrat Alegret  1 , Olalla Maroñas  5 , Juan Antonio Pineda  7 , Juan Macías  7 ; GR@ACE study group; DEGESCO consortium; Marta Marquié  1   2 , Sergi Valero  1   2 , Alba Benaque  1 , Jordi Clarimón  2   8 , Maria Jesus Bullido  2   9   10 , Guillermo García-Ribas  11 , Pau Pástor  12 , Pascual Sánchez-Juan  2   13 , Victoria Álvarez  14   15 , Gerard Piñol-Ripoll  2   16 , Jose María García-Alberca  17 , José Luis Royo  18 , Emilio Franco-Macías  19 , Pablo Mir  2   20 , Miguel Calero  2   21   22 , Miguel Medina  2   21 , Alberto Rábano  2   21   23 , Jesús Ávila  2   24 , Carmen Antúnez  25 , Luis Miguel Real  7   18 , Adelina Orellana  1 , Ángel Carracedo  5   26 , María Eugenia Sáez  6 , Lluís Tárraga  1   2 , Mercè Boada  1   2 , Carlos Cruchaga  3   4 , Agustín Ruiz  27   28 ; Alzheimer’s Disease Neuroimaging Initiative
Collaborators, Affiliations

Long runs of homozygosity are associated with Alzheimer's disease

Sonia Moreno-Grau et al. Transl Psychiatry. .

Abstract

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10-5; βFROH (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10-16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10-4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Schematic of the stepwise for ROH prioritization.
1. Identification of ROH segments per individual; 2. Estimation of: homozygosity parameters, and 3. Consensus ROHs; 4. Association analysis between: a) Homozygosity parameters and AD status, and b) Consensus ROH and AD status; 5. Identification of inbred AD cases and ROH prioritization; 6. Exploration of selected ROH segments in WES data applying: a) Gene-based strategy, and b) Variant filtering strategy.
Fig. 2
Fig. 2. Runs of homozygosity per cohort and per individual.
A Mean number of ROHs versus mean total sum of ROHs in Mb for the 10 cohorts explored. B Mean number of ROHs versus mean total sum of ROHs in Mb per individual explored. Red dashed lines represent the threshold for the inbreeding coefficient of 0.0156 (second cousins’ offspring) and 0.0625 (first cousins’ offspring).
Fig. 3
Fig. 3. Circos plot for the prioritized regions.
Histogram for the effect of the 21,190 consensus ROHs identified in the whole sample is shown. Risk ROH associations are shown in red; protective ROH associations are shown in green. Blue regions represent prioritized ROHs from consanguineous AD cases. Orange segments represent prioritized regions harboring potential recessive variants.
See this image and copyright information in PMC

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