Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3
Herold C, Hooli BV, Mullin K, Liu T, Roehr JT, Mattheisen M, Parrado AR, Bertram L et al.. Molecular psychiatry, 2016-02-02
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP, PSEN1, and PSEN2 cause a subset of early-onset familial AD. On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ɛ4 allele in the gene APOE, and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study, we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3500 subjects from 1070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value=3.98 × 10 -8 ), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10 -8 ), and rs1513625 near PDCL3 (P-value=4.28 × 10 -8 ). In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10 -7 ) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10 -7 ; rs62400067, P-value=3.54 × 10 -7 ). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance.
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APA 7th
Herold, C., Hooli, B. V., Mullin, K., Liu, T., Roehr, J. T., Mattheisen, M., et al. (2016). Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3. Molecular psychiatry. https://doi.org/10.1038/mp.2015.218
Vancouver
Herold C, Hooli BV, Mullin K, Liu T, Roehr JT, Mattheisen M, et al. Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3. Molecular psychiatry. 2016. doi:10.1038/mp.2015.218. PMID: 26830138.
BibTeX
@article{herold2016-26830138,
author = {Herold, C. and Hooli, B. V. and Mullin, K. and Liu, T. and Roehr, J. T. and Mattheisen, M. and Parrado, A. R. and Bertram, L. and others},
title = {{Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3}},
journal = {Molecular psychiatry},
year = {2016},
doi = {10.1038/mp.2015.218},
pmid = {26830138},
url = {https://doi.org/10.1038/mp.2015.218}
}
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Key findings
- Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated.
- Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value=3.98 × 10 -8 ), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10 -8 ), and rs1513625 near PDCL3 (P-value=4.28 × 10 -8 ).
- In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10 -7 ) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10 -7 ; rs62400067, P-value=3.54 × 10 -7 ).
- In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance.
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Study details
- Study designmeta-analysis
- Participants3,500
- Evidence strengthHigh
How this study scored 81/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. Scored zero for effect reported because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 47 of the 58 points we could judge it on, which is 81 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2016 — within 20 year(s) of the newest study here |
| Sample size | 3 / 4 | 3,500 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | A review of other studies — randomization is not credited here |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26830138) |
| Free to read | 2 / 2 | Free to read |
| Points | 47 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 47 of the 58 points we could judge it on is 81 out of 100. |
| Total | 81 / 100 | — |
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