One for all and all for One: Improving replication of genetic studies through network diffusion

Lancour, Daniel; Naj, Adam C.; Mayeux, Richard; Haines, Jonathan L.; Pericak‐Vance, Margaret A.; Schellenberg, Gerard; Crovella, Mark; Farrer, Lindsay A.; Kasif, Simon

doi:10.1371/journal.pgen.1007306

Cited by 25 publications

(22 citation statements)

References 77 publications

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“…Furthermore, a recent computational study indicated the association between the SHARPIN gene and AD. (Lancour et al, 2018) In this report, Lancour et al developed a novel integrated GWAS risk score with a network diffusion approach. They tested this approach on a large GWAS dataset from Caucasians with AD and identified SHARPIN as a possible AD risk gene with the second ranked risk score.…”

Section: Discussionmentioning

confidence: 99%

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

Asanomi¹,

Shigemizu²,

Miyashita³

et al. 2019

Mol Med

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Background Late-onset Alzheimer’s disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population. Methods To identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk. Results Via step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10 − 5 , odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses. Conclusions Our work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development. Electronic supplementary material The online version of this article (10.1186/s10020-019-0090-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

Asanomi¹,

Shigemizu²,

Miyashita³

et al. 2019

Mol Med

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“…Both variants have a relatively large effect ( Figure 5), which strongly suggests that SHARPIN is the culprit gene in the locus. SHARPIN was proposed as a candidate gene for AD by prioritisation of GWAS signals using protein network analysis 49 and by genetic association in the Japanese population 50 . In the Japanese study, a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg) was associated at suggestive significance with an increased risk of AD.…”

Section: Discussionmentioning

confidence: 99%

Common variants in Alzheimer’s disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

Rojas

Moreno‐Grau

Tesi

et al. 2019

Preprint

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BACKGROUND:Disentangling the genetic constellation underlying Alzheimer's disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS). METHODS:Three sets of summary statistics were included in our meta-GWAS of AD: an Spanish casecontrol study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inversevariance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of subthreshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study. FINDINGS:Using our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical ADcase control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10 -7 ), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10 -39 ). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12-4.18, p = 3.2×10 -10 ) increased risk compared to those with the 2% lowest risk (p = 5.9×10 -10 ). Using the PRS we identified APOE ɛ33 carriers with a similar risk as APOE ɛ4 heterozygotes carriers, as well as APOE ɛ4 heterozygote carriers with a similar risk as APOE ɛ4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10 -6 ); a 4-year median onset diff...

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“…Association of this variant with the history of AD in both parents, in an independent cohort, verifies its contribution to dementia heritability, since each parent shares half of their genomic constitution with the child. Two recent articles have implicated SHARPIN in AD, with a rare variant (minor allele frequency: 2×10 −4 ) in this gene found to increase the risk of AD to almost six fold, an effect larger than that of the TREM2 variant 19,20 . SHARPIN modulates recruitment of Kindlin-2, which is encoded by another AD risk gene, to the β1-integrin receptor, affecting signaling through the biological adhesion pathway 21 .…”

Section: Discussionmentioning

confidence: 99%

A Non-Synonymous SHARPIN Variant is Associated with Limbic Degeneration and Family History of Alzheimer’s Disease

Soheili-Nezhad

Jahanshad

Guelfi

et al. 2017

Preprint

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Mapping the spatiotemporal dynamics of brain atrophy in the Alzheimer's disease (AD) aids in discovering vulnerable brain networks. Various MRI-derived measures including hippocampal volume loss are commonly used as imaging biomarkers of AD progression. Multivariate methods such as independent component analysis (ICA) have recently shown promise in revealing more complex patterns of brain atrophy.Here, we aimed to extract a data-driven signature of brain atrophy in AD and its heralding risk factor, the mild cognitive impairment (MCI) state. Structural brain changes were quantified in 1,892 MRI scans from 1,100 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) by Tensor-Based Morphometry (TBM).Brain morphometry maps of this population were fed into an ICA-based feature extraction algorithm which revealed that AD is associated with a characteristic signature of brain degeneration spanning several areas of the limbic system. The highest probability of brain atrophy in AD was localized to amygdalae (pICA z-score>22), followed by hippocampus (pICA z-score>14), and the mammillary bodies (pICA z-score>9) together with their white-matter connections including fimbrial and fornical tracts as a unified MRI endophenotype. This endophenotype performed better than the hippocampal volume measure in discriminating both AD and MCI subjects from the cognitively normal group, and we evaluated the potential for this feature set to serve as a disease-related endophenotype in a whole-genome association study. A protein-altering polymorphism in the synaptic scaffold gene, SHARPIN, affected loss of volume in this endophenotype among 8,852,807 whole-genome sequencing-based variants (rs34173062; p =2.1×10 -10 ). Other suggestive but subgenome-wide signals mapped to EPHA7 and FRMD4A, two known AD risk loci.In conclusion, by unsupervised decomposition of brain morphometry maps, we have provided a unified imaging endophenotype of AD that closely maps to the brain's memory center. Observation of bilateral amygdalae as the most vulnerable limbic structures spotlights impairment of emotional and memory processing integration in early AD.

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One for all and all for One: Improving replication of genetic studies through network diffusion

Cited by 25 publications

References 77 publications

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

Common variants in Alzheimer’s disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

A Non-Synonymous SHARPIN Variant is Associated with Limbic Degeneration and Family History of Alzheimer’s Disease

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