GWAS on family history of Alzheimer’s disease

Marioni, Riccardo E.; Harris, Sarah E.; McRae, Allan F.; Zhang, Qian; Hagenaars, Saskia; Hill, W. David; Davies, Gail; Ritchie, Craig W.; Galé, Catharine R.; Starr, John M.; Goate, Alison; Porteous, David J.; Yang, Jian; Evans, Kathryn; Deary, Ian J.; Wray, Naomi R.; Visscher, Peter M.

doi:10.1101/246223

Cited by 65 publications

(125 citation statements)

References 57 publications

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“…This suggests that the AD-association of the MEF2C and FERMT2 variants might be false positive findings in previous studies. This is in line with results from unpublished GWASs of AD in which AD-associations of variants near the MEF2C and FERMT2 genes were not replicated 41,42 ( p = 5.4×10 −3,41 p = 3.0×10 −4 for MEF2C 42 and p = 1.6×10 −5 for FERMT2 42 variant, with 5.0×10 −8 being the genome-wide significance threshold). An additional strength of our study is that our cohorts of AD patients and controls, were not previously used in the discovery of any of the known AD associated variants; 4–17 we thus provide independent replication in a genetically homogeneous group of individuals, as they all came from one specific population (Dutch).…”

Section: Discussionsupporting

confidence: 87%

Centenarian Controls Increase Variant Effect-sizes by an average two-fold in an Extreme Case-Extreme Control Analysis of Alzheimer’s Disease

Tesi

Lee

Hulsman

et al. 2018

Preprint

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31The detection of genetic loci associated with Alzheimer's disease (AD) requires large 32 numbers of cases and controls because variant effect-sizes are mostly small. We 33 hypothesized that variant effect-sizes should increase when individuals who represent the 34 extreme ends of a disease spectrum are considered, as their genomes are assumed to be 35 maximally enriched or depleted with disease-associated genetic variants. 36We used 1,073 extensively phenotyped AD cases with relatively young age at onset as 37 extreme cases (66.3±7.9 years), 1,664 age-matched controls (66.0±6.5 years) and 255 38 cognitively healthy centenarians as extreme controls (101.4±1.3 years). We estimated the 39 effect-size of 29 variants that were previously associated with AD in genome-wide 40 association studies. 41Comparing extreme AD-cases with centenarian-controls increased the variant effect-size 42 relative to published effect-sizes by on average 1. ). The effect-43 size increase was largest for the rare high-impact TREM2 (R74H) variant (6.5-fold), and 44 significant for variants in/near ECHDC3 (4.6-fold), SLC24A4-RIN3 (4.5-fold), NME8 (3.8-45 fold), PLCG2 (3.3-fold), APOE-ε2 (2.2-fold) and APOE-ε4 (2.0-fold). Comparing extreme 46 phenotypes enabled us to replicate the AD association for 10 variants (p<0.05) in relatively 47 small samples. The increase in effect-sizes depended mainly on using centenarians as 48 extreme controls: the average variant effect-size was not increased in a comparison of 49 extreme AD cases and age-matched controls (0.94-fold, p=6.8x10 -1 ), suggesting that on 50 average the tested genetic variants did not explain the extremity of the AD-cases. 51Concluding, using centenarians as extreme controls in AD case-controls studies boosts the 52 variant effect-size by on average two-fold, allowing the replication of disease-association in 53 relatively small samples. 55Alzheimer's disease (AD) is characterized by a slow but progressive loss of cognitive 56 functions, leading to loss of autonomy. 1 AD is rare at the age of 65 years, but its incidence 57 increases exponentially to 40% at the age of 100 years. 2 It is currently the most prevalent 58 cause of death at old age and one of the major health threats of the 21st century. 1 Better 59 understanding of the etiological factors that determine AD is warranted as no treatment is 60 currently available. Heritability plays an important role as genetic factors are estimated to 61 determine 60-80% of the risk of AD. 3 About 30% of the genetic risk is attributable to the ε4 62 allele of APOE gene, and large collaborative efforts have identified over two dozen additional 63 genetic loci that are associated with a slight modification of the risk of AD. 4-17 The design of 64 these association studies relies on the comparison of very large numbers of cases with age- 65matched controls, such that detected associations can be attributed specifically to the 66 disease. 18 However, given the prevalence of AD in the aging population, it is likely that a 67 significant fracti...

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Section: Discussionsupporting

confidence: 87%

Centenarian Controls Increase Variant Effect-sizes by an average two-fold in an Extreme Case-Extreme Control Analysis of Alzheimer’s Disease

Tesi

Lee

Hulsman

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…The ADAMTS4 and KAT8 loci have also since been identified in a recent analysis in a partially overlapping sample. 13 Comparing our meta-analysis results with all loci of Lambert et al 4 to determine differences in associated loci, we were unable to observe 4 loci (MEF2C, NME8, CELF1 and FERMT2) at a GWS level (observed P-values were 1.6x10 -5 to 0.0011), which was mostly caused by a lower association signal in the UKB dataset (Supplementary Table 6). By contrast, Lambert et al 4 were unable to replicate the DSG2 and CD33 loci in the second stage of their study.…”

Section: Supplementary Figure 1 Supplementary Table 2)mentioning

confidence: 56%

“…As the proxy phenotype is not a pure measure of an individual's AD status and may include individuals that never develop AD, genetic effect sizes will be somewhat underestimated. However, the proxy case-control sample is very large, and therefore substantially increases power to detect genetic effects for AD 12 , as was also demonstrated in a more recent study using UKB 13 . Finally, in phase 3, we meta-analysed all individuals of phase 1 and phase 2 together and tested for replication in an independent sample.…”

Section: Introductionmentioning

confidence: 92%

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

et al. 2019

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Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 diseaseassociated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg=0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

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“…For example, female-or male-specific effects have been reported in ACE 16 , BDNF 17 and RELN 18 genes. Large-scale meta-analyses of genotyped data have largely focused on the AD affection status itself, rather than on sex-specific AD effects [19][20][21] . This may be attributed to the fact that understanding and modelling gene-by-environment interactions still remain major challenges in the field, due to lack of power given current analytic methods.…”

mentioning

confidence: 99%

Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

Prokopenko

Hecker

Kirchner

et al. 2020

Sci Rep

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With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer's Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (P inter = 1.83 × 10 −7 ), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.Alzheimer's disease (AD) is the most common form of dementia worldwide, with a substantial burden for not only patients, but their families, society and the healthcare system. The impact of the disease is expected to increase further by 2050, with a projected 13.9 million Americans to develop AD or related dementias 1 . Like most complex diseases, AD is caused by a mixture of genetic and environmental factors. Early-onset familial AD (monogenic) is caused by rare fully penetrant mutations in APP, PSEN1, PSEN2 genes 2 . The more prevalent form, late-onset (sporadic) AD, is caused by a complex polygenic architecture, including large-effect variants in the APOE gene 3 . Environmental and lifestyle factors also affect the prevalence of the disease, however this domain is less well elucidated to date. Although one of the strongest predictors for AD is age, there are several other risk factors, including race 4 , high blood pressure 5 , brain trauma 6 and sex 7-10 .Not only are women at twofold greater risk than men, the progression of the disease and neurodegeneration is more rapid among women versus men 11,12 . In contrast, men with AD have higher mortality, as compared to women 12,13 . Interactions between sex and APOE ε4 have been previously reported. For instance, Altmann et al. showed that women have greater AD risk in the presence of APOE ε4, and this APOE-related risk in women may

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GWAS on family history of Alzheimer’s disease

Cited by 65 publications

References 57 publications

Centenarian Controls Increase Variant Effect-sizes by an average two-fold in an Extreme Case-Extreme Control Analysis of Alzheimer’s Disease

Centenarian Controls Increase Variant Effect-sizes by an average two-fold in an Extreme Case-Extreme Control Analysis of Alzheimer’s Disease

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

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