Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

In the paper

“angiotensin II, a product of ACE function, mediates a number of neuropathological processes in Alzheimer’s disease84 and is now a target for intervention in phase II clinical trials of Alzheimer’s disease85.”

What the sources say

• Partly supported

  In “Additional roles of RAS in AD pathology: beyond blood pressure in AD” (page unavailable), the paper reports that angiotensin II worsened Aβ pathology and stimulated Aβ production and tau phosphorylation in rodent studies. “The imbalanced RAS in Alzheimer’s disease” describes its contribution to human AD pathology as a possibility, not an established causal finding. The phase II trial clause is attached to a different citation and is not judged here. (LLM, conf=0.84)

  cites [84] Kehoe, P. G. The coming of age of the angiotensin hypothesis in Alzheimer’s disease: progress toward disease prevention and treatment? J. Alzheimers. Dis. 62, 1443–1466 (2018). sourceExperimental — accuracy not yet measured
• Supported

  The Conclusion (page not available) identifies RADAR as a phase II study of losartan in patients with early Alzheimer’s disease. The Background (page not available) explains that losartan blocks angiotensin II signaling and that the trial tests this intervention in mild to moderate Alzheimer’s disease. (LLM, conf=0.93)

  cites [85] Kehoe, P. G. et al. The rationale and design of the reducing pathology in Alzheimer’s disease through Angiotensin TaRgeting (RADAR) Trial. J. Alzheimers. Dis. 61, 803–814 (2017). source

In the paper

“Meta-analysis of Stages 1 and 2 produced 21 genome-wide-significant associations (P ≤ 5 × 10−8) (Table 1 and Fig. 1), 18 of which were previously reported as genome-wide significant in Lambert et al.1.”

What the sources say

• Not checked yetcites [1] Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013). source

In the paper

“The Stage 1 discovery meta-analysis produced 12 loci with genome-wide significance (P ≤ 5 × 10−8) (Table 1), all of which are previously described1,4–11.”

What the sources say

• Not checked yetcites [1] Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013). source
• Not checked yetcites [4] Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 43, 436–441 (2011). source
• Not checked yetcites [5] Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303, 1832–1840 (2010). source
• Not checked yetcites [6] Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011). source
• Not checked yetcites [7] Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013). source
• Not checked yetcites [8] Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013). source
• Not checked yetcites [9] Jun, G. et al. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch. Neurol. 67, 1473–1484 (2010). source
• Not checked yetcites [10] Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009). source
• Not checked yetcites [11] Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009). source

In the paper

“There were no eQTLs in Alzheimer’s disease–relevant tissues in the WWOX or ACE locus, although several eQTLs for PSMC5 in coronary artery tissue were found for the ACE locus.”

In the paper

“Genes driving these enrichments (that is, having a gene-wide P < 0.05) included SCNA, a Parkinson’s risk gene that encodes alpha-synuclein, the main component of Lewy bodies, whch may play a role in tauopathies62,63, for the tau pathway; apolipoprotein genes (APOM, APOA5) and ABCA1, a major regulator of cellular cholesterol, for the lipid metabolism pathways; and 52 immune pathway genes”

What the sources say

• Not checked yetcites [62] Stefanis, L. alpha-Synuclein in Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, 1–23 (2012). source
• Not checked yetcites [63] Takeda, A. et al. C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders. Acta Neuropathol. 99, 296–304 (2000). source

In the paper

“When APOE-region genes and genes near genome-wide-significant genes were removed, tau showed moderate association (P = 0.027), and lipid metabolism and immune-related pathways showed strong associations (P < 0.001)”

In the paper

“Two of the four other signals approached genome-wide significance: miR142/TSPOAP1-AS1 (P = 5.3 × 10−8) and NDUFAF6 (P = 9.2 × 10−8) (Table 2).”

In the paper

“only 2% of 1,073 variants across the 24 loci (excluding APOE) were exonic variants, with a majority (58%) being intronic”

In the paper

“Co-localization analysis confirmed evidence of a shared causal variant affecting expression and disease risk in 66 genes over 20 loci, including 31 genes over 13 loci in LOAD-relevant tissue”

In the paper

“For our newly identified loci, there were significant eQTLs in Alzheimer’s disease–relevant tissue for ADAM10, FAM63B, and SLTM (in the ADAM10 locus); ADAMTS1 (ADAMTS1 locus); and ACSM1, ANKS4B, C16orf62, GDE1, GPRC5B, IQCK, and KNOP1 (IQCK locus).”

In the paper

“Nominal enrichment for risk from rare variants was found for the pathway ‘aggregation of Aβ: chaperone’ and 23 of the 335 genes.”

In the paper

“we found overlapping cis-acting eQTLs for 153 of the 400 protein-coding genes, with 136 eQTL-controlled genes in Alzheimer’s disease–relevant tissues”

In the paper

“Several ‘sub-pathways’ were also significantly enriched in the common variants, including ‘clearance and degradation of Aβ’, and ‘aggregation of Aβ’, along with its subcategory ‘microglia’”

In the paper

“replicated a low-frequency variant in the TREM2 region (rs114812713; NC_000006.11: g.41034000G>C, MAF = 0.03, P = 7.2 × 10−3; combined P = 2.1 × 10−13) in the gene OARD1 that may represent an independent signal according to our conditional analysis”

In the paper

“We observed significant enrichment of this gene set in common variants (P = 2.27 × 10−4; P = 3.19 × 10−4 excluding APOE), with both ADAM10 and ACE nominally significant drivers of this result”

In the paper

“When not considering fetal astrocytes, mature astrocytes (21%), and microglial cells (20.3%), the resident macrophage cells of the brain thought to play a key role in the pathologic immune response in LOAD8,14,60, became the highest expressed cell types in the genome-wide set of genes, with 5.3% of the 400 genes showing high microglial expression”

What the sources say

• Not checked yetcites [8] Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013). source
• Not checked yetcites [14] Sims, R. C. et al. Novel rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1387 (2017). source
• Not checked yetcites [60] Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015). source

In the paper

“While no pathways were significantly enriched for rare variants, lipid and Aβ pathways did reach nominal significance in rare-variant-only analyses.”

In the paper

“the sentinel variant (defined as the variant with the lowest P value) is just 2.4 mega-bases from PLCG2, which contains a rare variant that we recently associated with Alzheimer’s disease14.”

What the sources say

• Not checked yetcites [14] Sims, R. C. et al. Novel rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1387 (2017). source

In the paper

“we also observed a highly significant correlation between common and rare pathway gene results (P = 1.32 × 10−7), suggesting that risk Alzheimer’s disease genes and pathways are enriched for rare variants.”

In the paper

“80% were expressed in at least one type of brain cell, and the genes were most highly expressed in fetal astrocytes (26%), followed by microglia/ macrophages (15.8%), neurons (14.8%), astrocytes (11.5%), and oligodendrocytes (6.5%).”

In the paper

“Potentially deleterious variants include the rare R47H missense variant in TREM2, common missense variants in CR1, SPI1, MS4A2, and IQCK, and a relatively common (MAF = 0.16) splicing variant in IQCK.”

In the paper

“Stage 3A also extended the analysis of two loci (NME8 and MEF2C) that were previously genome-wide significant in our 2013 meta-analysis.”

In the paper

“Three other signals were not initially described in the initial IGAP GWAS: the rare R47H TREM2 coding variant previously reported by others7,8,14; ECHDC3 (rs7920721; NC_000010.10: g.11720308A>G), which was recently identified as a potential genome-wide-significant Alzheimer’s disease risk locus in several studies15–17, and ACE (rs138190086; NC_000017.10: g.61538148G>A)”

What the sources say

• Not checked yetcites [7] Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013). source
• Not checked yetcites [8] Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013). source
• Not checked yetcites [14] Sims, R. C. et al. Novel rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1387 (2017). source

In the paper

“we also identified ten genes located in our genome-wide loci as having rare deleterious coding, splicing or LOF burden associations with LOAD (false discovery rate (FDR) P < 0.01), including previously implicated rare-variant signals in ABCA7, TREM2, and SORL1 (refs. 14,49–55), and additional associations with TREML4 in the TREM2 locus, TAP2 and PSMB8 in the HLA-DRB1 locus, PIP in the EPHA1 locus,”

What the sources say

• Not checked yetcites [14] Sims, R. C. et al. Novel rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1387 (2017). source
• Not checked yetcites [49] Bis, J. C. et al. Whole exome sequencing study identifies novel rare and common Alzheimer’s-associated variants involved in immune response and transcriptional regulation. Mol. Psychiatry https://doi.org/10.1038/s41380-018-0112-7 (2018). source
• Not checked yetcites [50] Vardarajan, B. N. et al. Coding mutations in SORL1 and Alzheimer disease. Ann. Neurol. 77, 215–227 (2015). source
• Not checked yetcites [51] Verheijen, J. et al. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease. Acta Neuropathol. 132, 213–224 (2016). source
• Not checked yetcites [52] Bellenguez, C. et al. Contribution to Alzheimer’s disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol. Aging. 59, 220.e1–220.e9 (2017). source
• Not checked yetcites [53] Kunkle, B. W. et al. Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease. Neurosci. Lett. 649, 124–129 (2017). source
• Not checked yetcites [54] May, P. et al. Rare ABCA7 variants in 2 German families with Alzheimer disease. Neurol. Genet. 4, e224 (2018). source
• Not checked yetcites [55] Guennec, K. Le et al. ABCA7 rare variants and Alzheimer disease risk. Neurology 86, 1–4 (2016). source

In the paper

“These alleles form the HLA-DQA1*01:02~HLA-DQB1*06:02~HLA-DRB1*15:01 (DR15) haplotype, which is also associated with Alzheimer’s disease in our sample (FDR P = 0.013)”

In the paper

“Of the 22 genes in the ACE locus, PSMC5, a key regulator of major histocompatibility complex (MHC)75,76, has a top score of 4, while DDX42, MAP3K3, an important regulator of macrophages and innate immunity77,78, and CD79B, a B lymphocyte antigen receptor subunit, each have a score of 3.”

What the sources say

• Not checked yetcites [75] Bhat, K. et al. The 19S proteasome ATPase Sug1 plays a critical role in regulating MHC class II transcription. Mol. Immunol. 45, 2214–2224 (2008). source
• Not checked yetcites [76] Inostroza-Nieves, Y., Venkatraman, P. & Zavala-Ruiz, Z. Role of Sug1, a 19S proteasome ATPase, in the transcription of MHC I and the atypical MHC II molecules, HLA-DM and HLA-DO. Immunol. Lett. 147, 67–74 (2012). source
• Not checked yetcites [77] Kim, K., Duramad, O., Qin, X. F. & Su, B. MEKK3 is essential for lipopolysaccharide-induced interleukin-6 and granulocyte-macrophage colony-stimulating factor production in macrophages. Immunology 120, 242–250 (2007). source

In the paper

“the 53 genes are overexpressed in ‘adolescence’ and ‘young adult’ brain tissues in BrainSpan103, a transcriptomic atlas of the developing human brain, which is consistent with accumulating evidence suggesting Alzheimer’s disease may start decades before the onset of disease104,105”

What the sources say

• Not checked yetcites [103] Miller, J. A. et al. Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014). source
• Not checked yetcites [104] Knickmeyer, R. C. & Ross, M. E. Imaging and rare APOE alleles. Neurology 87, 558–559 (2016). source
• Not checked yetcites [105] Douaud, G. et al. A common brain network links development, aging, and vulnerability to disease. Proc. Natl Acad. Sci. USA 111, 17648–17653 (2014). source

In the paper

“Two additional alleles, HLA-DQA1*03:01 and HLA-DQB1*03:02, belonging to another haplotype, show a protective effect on Alzheimer’s disease, but their signal was lost after conditioning on HLA-DQA1*01:02, and the HLA-DQA1*03:01~HLA-DQB1*03:02 haplotype is not associated with Alzheimer’s disease (FDR P = 0.651).”

In the paper

“WWOX and MAF, which surround an intergenic signal in an obesity associated locus91, were both prioritized for the WWOX locus, with MAF, another important regulator of macrophages92,93, being highly expressed in microglia in the Brain RNA-seq database, and WWOX, a high-density-lipoprotein cholesterol and triglyceride–associated gene94,95, being expressed most highly in astrocytes and neurons.”

What the sources say

• Not checked yetcites [91] Wang, K. et al. A genome-wide association study on obesity and obesity-related traits. PLoS ONE 6, 3–8 (2011). source
• Not checked yetcites [92] Kang, K. et al. Interferon-γ represses M2 gene expression in human macrophages by disassembling enhancers bound by the transcription factor MAF. Immunity 47, 235–250.e4 (2017). source
• Not checked yetcites [93] Cao, S., Liu, J., Song, L. & Ma, X. The protooncogene c-Maf Is an essential transcription factor for IL-10 gene expression in macrophages. J. Immunol. 174, 3484–3492 (2005). source

In the paper

“However, these studies yielded inconsistent results23, and our work reports a clear genome-wide association in NHW at this locus.”

What the sources say

• Not checked yetcites [23] Wang, X.-B. et al. Angiotensin-converting enzyme insertion/deletion polymorphism is not a major determining factor in the development of sporadic Alzheimer disease: evidence from an updated meta-analysis. PLoS ONE 9, e111406 (2014). source

In the paper

“we identified significant differential expression in several potentially relevant Alzheimer’s disease tissues including immune-related tissues (upregulation in blood and spleen), obesity-related tissue (upregulation in adipose), heart tissues (upregulation in left ventricle and atrial appendage), and brain tissues (dowregulation in cortex, cerebellum, hippo-campus, basal ganglia, and amygdala).”

In the paper

“We found risk effects of HLA-DQA1*01:02 (FDR P = 0.014), HLA-DRB1*15:01 (FDR P = 0.083), and HLA-DQB1*06:02 (FDR P = 0.010)”

In the paper

“After conditioning on the sentinel meta-analysis variant in this region (rs78738018), association signals were lost for the three alleles, suggesting that the signal observed at the variant level is due to the association of these three alleles.”

In the paper

“For the IQCK signal, which is also an obesity locus70,71, IQCK, a relatively uncharacterized gene, was ranked top, although four of the other 11 genes in the locus have a priority rank ≥ 4, including KNOP1 and GPRC5B”

What the sources say

• Not checked yetcites [70] Hinney, A. et al. Genetic variation at the CELF1 (CUGBP, elav-like family member 1 gene) locus is genome-wide associated with Alzheimer’s disease and obesity. Am. J. Med. Genet. B. 165B, 283–293 (2014). source
• Not checked yetcites [71] Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010). source

In the paper

“Pathway, tissue and disease trait enrichment analyses support the utility of our prioritization method, as the 53 prioritized genes with a score ≥ 5 are (1) enriched in substantially more Alzheimer’s disease–relevant pathways, processes and dementia-related traits; (2) enriched in candidate Alzheimer’s disease cell types such as monocytes (adjusted P = 9.0 × 10−6) and macrophages (adjusted P = 5.6”

In the paper

“use of blood pressure medication does show a negative genetic correlation with Alzheimer’s disease in our study (rg = −0.12; P = 0.035), although this result does not survive FDR correction.”

In the paper

“The average size of the LD blocks was 123 kb.”

In the paper

“A total of 1,180,989 variants were used in the correlation analyses.”

In the paper

“After imputation quality control, a total of 14,776 cases and 23,047 controls were available for analysis (Supplementary Table 27).”

In the paper

“Removal of the APOE region reduced the heritability estimate slightly from 0.071 (s.e.m. = 0.011) to 0.0637 (s.e.m. = 0.009).”

In the paper

“univariate linkage disequilibrium score (LDSC) regression12,13 estimates indicated that the majority of this inflation was due to a polygenic signal, with the intercept being close to 1 (1.026, s.e.m. = 0.006).”

What the sources say

• Not checked yetcites [12] Zheng, J. et al. LD Hub: A centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics 33, 051094 (2017).
• Not checked yetcites [13] Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015). source

In the paper

“ACE and ADAM10 were previously reported as Alzheimer’s disease candidate genes18–22 but were not replicated in some subsequent studies23–25.”

What the sources say

• Not checked yetcites [18] Vassar, R. ADAM10 prodomain mutations cause late-onset Alzheimer’s disease: not just the latest FAD. Neuron 80, 250–253 (2013). source
• Not checked yetcites [19] Kim, M. et al. Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity. Hum. Mol. Genet. 18, 3987–3996 (2009). source
• Not checked yetcites [20] Kehoe, P. G. et al. Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat. Genet. 21, 71–72 (1999). source
• Not checked yetcites [21] Meng, Y. et al. Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community. Am. J. Hum. Genet. 78, 871–877 (2006). source
• Not checked yetcites [22] Lehmann, D. J. et al. Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer’s disease. Am. J. Epidemiol. 162, 305–317 (2005). source
• Not checked yetcites [23] Wang, X.-B. et al. Angiotensin-converting enzyme insertion/deletion polymorphism is not a major determining factor in the development of sporadic Alzheimer disease: evidence from an updated meta-analysis. PLoS ONE 9, e111406 (2014). source
• Not checked yetcites [24] Cai, G. et al. Evidence against a role for rare ADAM10 mutations in sporadic Alzheimer disease. Neurobiol. Aging. 33, 416–417.e3 (2012).
• Not checked yetcites [25] Belbin, O. et al. A multi-center study of ACE and the risk of late-onset Alzheimer’s disease. J. Alzheimers. Dis. 24, 587–597 (2011). source

In the paper

“WWOX may play a role in Alzheimer’s disease through its interaction with tau28,29”

What the sources say

• Not checked yetcites [28] Chang, J.-Y. & Chang, N.-S. WWOX dysfunction induces sequential aggregation of TRAPPC6AΔ, TIAF1, tau and amyloid β, and causes apoptosis. Cell Death Discov. 1, 15003 (2015). source
• Not checked yetcites [29] Sze, C. I. et al. Down-regulation of WW domain-containing oxidoreductase induces tau phosphorylation in vitro: a potential role in Alzheimer’s disease. J. Biol. Chem. 279, 30498–30506 (2004). source

In the paper

“ADAM10, the most important α-secretase in the brain, is a component of the non-amyloidogenic pathway of APP metabolism67 and sheds TREM2 (ref. 68)”

What the sources say

• Not checked yetcites [67] Haass, C., Kaether, C., Thinakaran, G. & Sisodia, S. Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2, a006270 (2012). source
• Not checked yetcites [68] Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med. 6, 243ra86 (2014). source

In the paper

“Overexpression of ADAM10 in mouse models can halt Aβ production and subsequent aggregation69.”

What the sources say

• Not checked yetcites [69] Postina, R. et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113, 1456–1464 (2004). source

In the paper

“Previous analyses in the ADGC (5,728 Alzheimer’s disease cases and 5,653 controls) have linked both HLA class I and II haplotypes with Alzheimer’s disease risk106.”

What the sources say

• Not checked yetcites [106] Steele, N. Z. et al. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: a case-control study. PLoS Med. 14, 1–25 (2017). source

In the paper

“the DR15 haplotype and its component alleles also associate with protection against diabetes108, a high risk for multiple sclerosis109,110, and risk or protective effects with many other immune-mediated diseases”

What the sources say

• Not checked yetcites [108] Pugliese, A. et al. HLA-DRB1 15:01-DQA1 01:02-DQB1 06:02 haplotype protects autoantibody-positive relatives from type 1 diabetes throughout the stages of disease progression. Diabetes 65, 1109–1119 (2016). source
• Not checked yetcites [109] Patsopoulos, Na et al. Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet. 9, e1003926 (2013). source
• Not checked yetcites [110] Schmidt, H., Williamson, D. & Ashley-Koch, A. HLA-DR15 haplotype and multiple sclerosis: a HuGE review. Am. J. Epidemiol. 165, 1097–1109 (2007). source

In the paper

“two rare ADAM10 alterations segregating with disease in LOAD families increased Aβ plaque load in ‘Alzheimer-like’ mice, with diminished α-secretase activity from the alterations probably the causal mechanism19,44.”

What the sources say

• Not checked yetcites [19] Kim, M. et al. Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity. Hum. Mol. Genet. 18, 3987–3996 (2009). source
• Not checked yetcites [44] Suh, J. et al. ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 80, 385–401 (2013). source

In the paper

“research shows dementia risk to be associated with lower socio-economic status, independently of education status118,119.”

What the sources say

• Not checked yetcites [118] Cadar, D. et al. Individual and area-based socioeconomic factors associated with dementia incidence in England: evidencefrom a 12-year follow-up in the English longitudinal study of ageing. JAMA Psychiatry 75, 723–732 (2018). source
• Not checked yetcites [119] Marden, J. R., Tchetgen Tchetgen, E. J., Kawachi, I. & Glymour, M. M. Contribution of socioeconomic status at 3 life-course periods to late-life memory function and decline: early and late predictors of dementia risk. Am. J. Epidemiol. 186, 805–814 (2017). source

In the paper

“While ACE was not prioritized, it should not be rejected as a candidate gene, as its expression in Alzheimer’s disease brain tissue is associated with Aβ load and Alzheimer’s disease severity80.”

What the sources say

• Not checked yetcites [80] Miners, J. S. et al. Angiotensin-converting enzyme levels and activity in Alzheimer’s disease: differences in brain and CSF ACE and association with ACE1 genotypes. Am. J. Transl. Res. 1, 163–177 (2009).

In the paper

“WWOX has been implicated in several neurological phenotypes96; in addition, it binds tau and may play a critical role in regulating tau hyper-phosphorylation, neurofibrillary formation and Aβ aggregation28,29.”

What the sources say

• Not checked yetcites [96] Chang, H. T. et al. WW domain-containing oxidoreductase in neuronal injury and neurological diseases. Oncotarget 5, 11792–11799 (2014). source
• Not checked yetcites [28] Chang, J.-Y. & Chang, N.-S. WWOX dysfunction induces sequential aggregation of TRAPPC6AΔ, TIAF1, tau and amyloid β, and causes apoptosis. Cell Death Discov. 1, 15003 (2015). source
• Not checked yetcites [29] Sze, C. I. et al. Down-regulation of WW domain-containing oxidoreductase induces tau phosphorylation in vitro: a potential role in Alzheimer’s disease. J. Biol. Chem. 279, 30498–30506 (2004). source

In the paper

“the associated diseases include a large number of traits queried from an HLA-specific Phewas111, including neurological diseases (for example, Parkinson’s disease112,113) and diseases with risk factors for Alzheimer’s disease (for example, hyperthyroidism114), pointing to potential shared and/or interacting mechanisms and co-morbidities”

What the sources say

• Not checked yetcites [111] Karnes, J. H. et al. Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. Sci. Transl. Med. 9, 1–14 (2017). source
• Not checked yetcites [112] Wissemann, W. T. et al. Association of Parkinson disease with structural and regulatory variants in the HLA region. Am. J. Hum. Genet. 93, 984–993 (2013). source
• Not checked yetcites [113] Misra, M. K., Damotte, V. & Hollenbach, J. A. The immunogenetics of neurological disease. Immunology 153, 399–414 (2018). source

In the paper

“Of three genes at this locus, our analyses nominate ADAMTS1 as the likely risk gene, although we cannot rule out that this signal is a regulatory element for APP.”

In the paper

“the latter being a regulator of neurogenesis72,73 and inflammatory signaling in obesity74.”

What the sources say

• Not checked yetcites [72] Kurabayashi, N., Nguyen, M. D. & Sanada, K. The G protein-coupled receptor GPRC5B contributes to neurogenesis in the developing mouse neocortex. Development 140, 4335–4346 (2013). source
• Not checked yetcites [73] Cool, B. H. et al. A flanking gene problem leads to the discovery of a Gprc5b splice variant predominantly expressed in C57BL/6J mouse brain and in maturing neurons. PLoS ONE 5, e10351 (2010). source
• Not checked yetcites [74] Kim, Y.-J., Sano, T., Nabetani, T., Asano, Y. & Hirabayashi, Y. GPRC5B activates obesity-associated inflammatory signaling in adipocytes. Sci. Signal. 5, ra85–ra85 (2012).

In the paper

“cerebrospinal fluid (CSF) levels of the angiotensin-converting enzyme (ACE) are associated with Aβ levels81 and LOAD risk82, and studies show ACE can inhibit Aβ toxicity and aggregation83.”

What the sources say

• Not checked yetcites [81] Jochemsen, H. M. et al. The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease. Alzheimers Res. Ther. 6, 1–10 (2014). source
• Not checked yetcites [82] Kauwe, J. S. K. et al. Genome-wide association study of CSFl Levels of 59 Alzheimer’s disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet. 10, e1004758 (2014). source
• Not checked yetcites [83] Baranello, R. J. et al. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr. Alzheimers Res 12, 32–46 (2015). source

In the paper

“similar to the Marioni et al. family proxy analyses26, which found maternal genetic correlation with Alzheimer’s disease to be higher than that for paternal Alzheimer’s disease (rg = 0.91 and 0.66, respectively).”

What the sources say

• Not checked yetcites [26] Marioni, R. E. et al. GWAS on family history of Alzheimeras disease. Transl. Psychiatry 8, 99 (2018). source

In the paper

“ADAMTS1 is elevated in Down’s syndrome with neurodegeneration and Alzheimer’s disease86, and it is a potential neuroprotective gene87–89 or a neuroinflammatory gene important to microglial response90.”

What the sources say

• Not checked yetcites [86] Miguel, R. F., Pollak, A. & Lubec, G. Metalloproteinase ADAMTS-1 but not ADAMTS-5 is manifold overexpressed in neurodegenerative disorders as Down syndrome, Alzheimer’s and Pick’s disease. Brain. Res. Mol. Brain. Res. 133, 1–5 (2005). source
• Not checked yetcites [87] Suttkus, A. et al. Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress. Cell Death Dis. 5, e1119 (2014). source
• Not checked yetcites [88] Végh, M. J. et al. Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 2, 76 (2014).
• Not checked yetcites [89] Morawski, M., Filippov, M., Tzinia, A., Tsilibary, E. & Vargova, L. ECM in brain aging and dementia. Prog. Brain. Res. 214, 207–227 (2014). source
• Not checked yetcites [90] Wilcock, D. M. Neuroinflammation in the aging down syndrome brain; lessons from Alzheimer’s disease. Curr. Gerontol. Geriatr. Res. 2012, 170276 (2012). source

In the paper

“Candidate gene studies have associated ACE variants with Alzheimer’s disease risk20,22,79, including a strong association in the Wadi Ara, an Israeli Arab community with high risk of Alzheimer’s disease21.”

What the sources say

• Not checked yetcites [20] Kehoe, P. G. et al. Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat. Genet. 21, 71–72 (1999). source
• Not checked yetcites [22] Lehmann, D. J. et al. Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer’s disease. Am. J. Epidemiol. 162, 305–317 (2005). source
• Not checked yetcites [79] Farrer, L. A. et al. Association between angiotensin-converting enzyme and Alzheimer disease. New Engl. J. Med. 57, 210–214 (2000).

In the paper

“treatment of mice with its binding partner restores memory deficits97”

What the sources say

• Not checked yetcites [97] Lee, M. H. et al. Zfra restores memory deficits in Alzheimer’s disease triple-transgenic mice by blocking aggregation of TRAPPC6AΔ, SH3GLB2, tau, and amyloid β, and inflammatory NF-κB activation. Alzheimers Dement. Transl. Res. Clin. Interv 3, 189–204 (2017). source

In the paper

“Before analyses in LD Hub, we removed all SNPs with extremely large effect sizes including the MHC (Chr6:26,000,000–34,000,000) and APOE region, as outliers can overly influence the regression analyses.”

In the paper

“The FDR threshold was set to 10%.”

In the paper

“Adjusted P values were computed using the FDR method and the R ‘p.adjust’ function, and applied to the meta-analysis P values.”

In the paper

“Per-study analysis for Stage 2 and Stage 3 followed the same analysis procedures described for Stage 1, except for covariate adjustments per cohort, where all analyses were adjusted on sex and age apart from the Italian, Swedish, and Gr@ACE cohorts, which were also adjusted for principal components.”

In the paper

“Alleles with an imputation posterior probability lower than 0.5 were considered as undetermined as recommended by HIBAG developers.”

In the paper

“We also required the presence of each variant in 30% of cases and 30% of controls across all datasets.”

In the paper

“Sex mismatches or individuals showing a high degree of relatedness (identical-by-descent value of 0.98 or greater) were removed from the analysis.”

In the paper

“Within-study results for Stage 1 were meta-analyzed in METAL141 using an inverse-variance-based model with genomic control.”

In the paper

“Genomic inflation was calculated for lambda (λ) in the GenABEL package142.”

In the paper

“Individuals with more than two undetermined HLA alleles were excluded.”

In the paper

“Standard quality control was performed on all datasets individually, including exclusion of individuals with low call rate, individuals with a high degree of relatedness, and variants with low call rate.”

In the paper

“We used the q value, which is the adjusted P value using the Benjamini–Hochberg FDR method with a 5% cutoff for correction for multiple hypotheses testing.”

In the paper

“Adaptive permutation was used to produce an empirical P value and an FDR-corrected q value.”

In the paper

“Per-sample quality checks for genetic sex and relatedness were performed in PLINK.”

In the paper

“A panel of ancestry-informative markers was used to perform principal component analysis with SMARTPCA from EIGENSOFT 4.2 software145, and individuals with non-European ancestry were excluded.”

In the paper

“Family datasets were tested using GWAF140, with generalized estimating equations (GEE) implemented for common variants (MAF ≥ 0.01), and a general linear mixed effects model (GLMM) implemented for rare variants (MAF < 0.01), per our preliminary data showing that the behavior of the test statistics for GEE was fine for common variants but inflated for rare variants, while GLMM controlled this rare-”

In the paper

“Associations of HLA alleles with disease were tested using logistic regressions, adjusting for age, sex, and principal components as specified above for single variant association analysis.”

In the paper

“All 400 protein-coding genes within our LD-defined genome-wide loci were annotated with the gene-based results from this study, and the results were corrected using a 1% FDR P as a cutoff for significance.”

In the paper

“Genes located less than 1 Mb from the GWAS sentinel variants that pass a 5% Benjamini–Hochberg FDR-corrected SMR P-value significance threshold and a HEIDI P-value > 0.05 threshold were considered significant.”

In the paper

“Splicing variants with high splicing potential according to MaxEntScan159 and protein-coding variants predicted to be deleterious by two or more programs were considered to be potentially causal variants for a locus.”

In the paper

“Statistical significance of the genetic correlations was estimated using 5% Benjamini−Hochberg FDR corrected P values.”

In the paper

“For haplotypes analysis, only individuals with no undetermined HLA alleles and only datasets with more than 100 cases or controls were included.”

In the paper

“It should be noted that while we do include rare variants from imputation in our analyses, we may be missing many rare causal variants in this study.”

In the paper

“In addition, we performed LDSC regression via LD Hub v.1.9.0 (refs. 12,13) to calculate the LD score regression intercept and derive a heritability estimate for the inverse-variance weighted meta-analysis summary statistics.”

What the sources say

• Not checked yetcites [12] Zheng, J. et al. LD Hub: A centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics 33, 051094 (2017).
• Not checked yetcites [13] Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015). source

In the paper

“The individuals in the ADSP study largely overlap with individuals in the ADGC and CHARGE cohorts included in our Stage 1 meta-analysis.”

In the paper

“Individuals with non-European ancestry according to principal components analysis of ancestry-informative markers were excluded from the further analysis.”

In the paper

“Variants with regression coefficient |β| > 5 or P value equal to 0 or 1 were excluded from further analysis.”

In the paper

“Significant enrichment was defined by Bonferonni-corrected P ≤ 0.05.”

In the paper

“Common variants (MAF ≥ 0.01%) with an r2 or an information measure <0.40 from MaCH and IMPUTE2 were excluded from further analyses.”

In the paper

“These datasets, conducted in whole blood, are large eQTL studies (Westra: discovery phase n = 5,311, replication phase n = 2,775; CAGE: n = 2,765), and while there is some overlap in samples between the two datasets, CAGE provides finer coverage.”

In the paper

“Stage 1 single variant-based association analysis employed an additive genotype model adjusting for age (defined as age-at-onset for cases and age-at-last exam for controls), sex, and population substructure using principal components138.”

In the paper

“Genes with a Bonferonni-corrected P < 0.05 and absolute log(fold change) ≥ 0.58 were considered DEGs.”

In the paper

“The APOE region (Chr19:45,116,911–46,318,605) was removed to calculate the intercept.”

In the paper

“For Stages 1, 2, and 3, samples did not overlap.”

In the paper

“Variant quality control was also performed separately in each country including removal of variants missing in more than 10% of individuals, having a Hardy−Weinberg P value in controls lower than 1 × 10−6 or a P value for missingness between cases and controls lower than 1 × 10−6.”

In the paper

“Rare variants (MAF < 0.01%) with a ‘global’ weighted imputation quality score of <0.70 were also excluded from analyses.”

In the paper

“Haplotype estimations and association analyses with disease were performed using the ‘haplo.glm’ function from the haplo.stats R package185 with age, sex, and principal components as covariates.”

In the paper

“Adjustments on HLA significant variants and HLA alleles were performed by introducing the variant or alleles as covariates in the regression models.”