Beyond GWAS: Investigating Structural Variants and Their Segregation in Familial Alzheimer’s Disease

Abstract Background Late‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated. Method We analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset. Result We identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene. Conclusion Our findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.

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Journal
Alzheimer s & Dementia
Published
2024-12-01
DOI
https://doi.org/10.1002/alz.092677
Primary Topic
Health, Environment, Cognitive Aging
Type
article
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article

Beyond GWAS: Investigating Structural Variants and Their Segregation in Familial Alzheimer’s Disease

Martin Medrano, Alexi Runnels, Clifton L. Dalgard, Anna O. Basile et al.
Alzheimer s & Dementia
Health, Environment, Cognitive Aging
article

Beyond GWAS: Investigating Structural Variants and Their Segregation in Familial Alzheimer’s Disease

Martin Medrano, Alexi Runnels, Clifton L. Dalgard, Anna O. Basile, Diones Rivera Mejía, Jonathan L. Haines, Tamil Iniyan Gunasekaran, Michael C. Zody, Carlos C Cruchaga, Debby W. Tsuang, Marta Byrska-Bishop, Rajeeva Musunuri, André Corvelo, R. J. Wilson, Bradley F. Boeve, Margaret Ann Pericak‐Vance, Roger N. Rosenberg, Richard P Mayeux, Uday S. Evani, Wayne E. Clarke, Giuseppe Narzisi, Robert A. Sweet, Alison Goate, Badri Narayan Vardarajan, Dolly Reyes‐Dumeyer, Rafael Lantigua, Kelley M. Faber, Tatiana M. Foroud, David A. Bennett
article en

Abstract

Abstract Background Late‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated. Method We analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset. Result We identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene. Conclusion Our findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.

Alzheimer s & DementiaVol. 20(S2)
Rush University Medical Center (US), Allen Institute for Brain Science (US), Mayo Clinic (US), NewYork–Presbyterian Hospital (US), Uniformed Services University of the Health Sciences (US), Pontificia Universidad Católica Madre y Maestra (DO), University of Pittsburgh (US), University of Washington (US), Washington University in St. Louis (US), Columbia University Irving Medical Center (US), New York Hospital Queens (US), WinnMed (US), Instituto Tecnológico de Santo Domingo (DO), VA Puget Sound Health Care System (US), Geriatric Research Education and Clinical Center (US), Universidad Nacional Pedro Henríquez Ureña (DO), Dr. John T. Macdonald Foundation (US), New York Genome Center (US), University School (US), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US), Case Western Reserve University (US), Columbia University (US), The University of Texas Southwestern Medical Center (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 65%
Health, Environment, Cognitive Aging
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