Details

Autor(en) / Beteiligte

• da Fonseca, Eder Lucio
• Jean‐Francois, Melissa N.
• Kurup, Jiji Thulaseedhara
• Slifer, Susan H.
• Martin, Eden R.
• Kunkle, Brian W.
• Schellenberg, Gerard D.
• Pericak‐Vance, Margaret A.
• Fernandez, Victoria
• Cruchaga, Carlos
• Reitz, Christiane
• Beecham, Gary W.

Titel

Heritability analyses show partial genetic overlap between (non‐Mendelian) early and late onset Alzheimer disease due to an intriguing APOE effect

Ist Teil von

• Alzheimer's & dementia, 2021-12, Vol.17 (S3), p.e056143-n/a

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Background Alzheimer disease (AD) is a degenerative brain disease, being the most common cause of progressive dementia and listed as the sixth leading cause of mortality in the USA. It is often described as either early onset (EOAD, age at onset, [AAO] <= 65) or late onset (LOAD, [AAO]>65). Non‐Mendelian EOAD (not monogenic; nmEOAD) has irregular inheritance patterns and fluctuating AAO, characteristics also present in LOAD cases. There is still a lack of evidence in the literature depicting the similarities (if any) between nmEOAD and LOAD forms, being unclear how much genetic etiology is shared by the two forms of AD. To shed light to this question, a genome‐wide association study (GWAS) and heritability analyses of nmEOAD and LOAD were performed. Method Genetic data on 21,622 individuals from the Alzheimer Disease Genetics Consortium (ADGC) were used: (1,476 nmEOAD, 9,695 LOAD and 10,451 control). Single‐variant association analyses were performed using logistic regression under two models: (1) ancestry plus SNP, and (2) ancestry, sex, APOE dosage, and SNP. nmEOAD and LOAD were considered separately. LD score regression was used to estimate the SNP heritability (h2) and genetic correlation (rg), considering two additional models: (3) ancestry, sex, and SNP and (4) ancestry, APOE dosage and SNP. Result Several known candidate genes confirmed for LOAD along with novel regions associated with immune and cell‐signaling pathways in nmEOAD models. Gene based tests showed significant association for APOE gene (Chr19): nmEOAD (p=3.89x10‐16 and p=4.29x10‐12) and LOAD (p=1.07x10‐65 and p=1.12x10‐14), models (1) and (2) respectively. Heritability analyses showed higher h2 values for EOAD (h2=0.24, 0.23, 0.25 and 0.24) than LOAD (h2=0.18, 0.14, 0.18, and 0.14) for models (1) to (4) respectively. Genetic correlation showed moderate genetic overlap between EOAD and LOAD only for models: (2) rg=0.35 (p=0.0283) and (4) rg=0.34 (p=0.0261). Conclusion GWAS and heritability analysis suggest that the genetic etiology of EOAD has a noncomplete genetic overlap with LOAD, with a moderate overlap when APOE dosage is modeled and a minimal overlap otherwise (APOE effect). The results also suggest a stronger polygenic effect in EOAD than LOAD, confirming the need for additional genomics efforts in nmEOAD.