Follow-up of loci from the International Genomics of Alzheimer’s Disease Project identifies TRIP4 as a novel susceptibility gene

Ruiz, Agustín; Heilmann, Stefanie; Becker, Tim; Hernández, Isabel; Wagner, Holger; Thelen, M.; Mauleón, Ana; Rosende-Roca, Maiteé; Bellenguez, Céline; Bis, Joshua C.; Harold, Denise; Gerrish, Amy; Sims, Rebecca; Sotolongo-Grau, Óscar; Espinosa, Ana; Alegret, Monserrat; Arrieta, J. López; Lacour, André; Leber, Markus; Becker, Jéssica; Lafuente, Asunción; Ruiz, Susana; Vargas, Liliana; Rodríguez, Octavio; Ortega, Gemma; Domínguez, M. Martínez; Mayeux, Richard; Haines, Jonathan L.; Pericak‐Vance, Margaret A.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Chouraki, Vincent; Launer, Lenore J.; Duijn, Cornelia M. van; Seshadri, Sudha; Antúnez, Carmen; Breteler, Monique M.B.; Serrano-Rı́os, Manuel; Jessen, Frank; Tárraga, Lluís; Nöthen, Markus M.; Maier, Wolfgang; Boada, Merçé; Ramı́rez, Alfredo

doi:10.1038/tp.2014.2

Cited by 86 publications

(64 citation statements)

References 19 publications

(23 reference statements)

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“…Among these, SORL1 had been identified in a GWAS of Japanese, Korean, and Caucasian AD cases and controls (the lattermost taken from the ADGC), however, as a well-established functional candidate, it had not been observed in a GWAS of European ancestry until the IGAP analyses, likely due to its low minor allele frequency (MAF) of ~0.04. Subsequent replication efforts have provided confirmation of the signal in ZCWPW1 (Ruiz et al, 2014) as well as evidence of association at TRIP4 . Multiple validation studies (studies examining associations among different ethnicities) in Southeast Asian populations have demonstrated associations at many of these loci: CLU (Komatsu et al, 2011; Liu et al, 2014; Yu et al, 2013), CR1 (Jin et al, 2012), PICALM (Chung et al, 2013; Liu et al, 2013; Miyashita et al, 2013), BIN1 (Liu et al, 2013; Miyashita et al, 2013), and the MS4A gene cluster (Deng et al, 2012; Tan et al, 2013).…”

Section: Genetics Of Alzheimer Disease: Late-onset Alzheimer Disease mentioning

confidence: 89%

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Naj

Schellenberg

2016

American J of Med Genetics Pt B

165

125

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Alzheimer’s disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world’s population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately ~20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses. Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple low-frequency and rare variant contributors to AD, and discuss on-going efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.

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Section: Genetics Of Alzheimer Disease: Late-onset Alzheimer Disease mentioning

confidence: 89%

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Naj

Schellenberg

2016

American J of Med Genetics Pt B

165

125

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“…In addition, 2 novel loci, TP53INP1 (p = 1.4 × 10− 6 ) and IGHV1-67 (p = 7.9 × 10− 8 ), showed genome-wide association for disease [13] (table 1). More recently, TRIP4 (p = 9.74 × 10− 9 ) has been confirmed as an AD risk locus when single nucleotide polymorphism (SNP) data from the IGAP data set was combined with data from additional genotyping in an independent sample (Fundació ACE data set; 1,808 patients and 2,564 controls) [14] (table 1). Also of note is PLD3; gene burden analysis of PLD3 variants showed a significant association with disease, suggesting that multiple variants in the gene contribute to disease [15].…”

Section: Genetic Findingsmentioning

confidence: 99%

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Sims

Williams²

2015

Neurodegener Dis

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Background: Late-onset Alzheimer's disease is a genetically complex disorder. For 17 years, APOE was the only known susceptibility gene for disease. Through mostly genome-wide association studies, 25 loci are now known to associate with late-onset Alzheimer's disease. These susceptibility loci are not randomly distributed with respect to their functions. In fact, pathway analysis implicates significant enrichment of immunity, endocytosis, cholesterol metabolism, and ubiquitination in disease. Summary: Twenty-five loci have now been reliably shown to associate with Alzheimer's disease. However, a significant proportion of genetic variation in disease pathology is yet to be detected. Rare variation is being investigated through exome chip and next-generation sequencing experiments, which have already identified new protective and risk variants. Using a polygenic risk score approach, it is now possible to identify population groups with the greatest and fewest biological susceptibilities to disease. This method has proved more effective in predicting disease status than individual, genome-wide significant variants of small/moderate effect. Future studies will establish the specific functional changes that contribute to disease by piloting novel cellular modelling techniques using reprogrammed induced pluripotent stem cells from individuals with selected risk profiles. This will allow a variety of models to be produced to help understand disease mechanisms and test new drug therapies. Key Messages: Alzheimer's disease is a polygenic trait that has been linked to deficits in immunity, endocytosis, cholesterol metabolism and ubiquitination. Future work will focus on identifying rare disease susceptibility loci, unpicking the functional significance of the known risk loci and piloting novel cellular modelling techniques.

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“…Through genome-wide association studies (GWASs), around 20 genetic loci had been discovered, which affect risk of LOAD (Lambert et al, 2013). Follow-up studies based on the GWAS have identified other potential candidate AD risk genes not previously identified, including the TRIP4, SPPL2A (Ruiz et al, 2014), and ABI3 genes (Sims et al, 2017). Next-generation sequencing has also enabled the identification of rare variants, one of the most consistent being the R47H variant in the TREM2 gene locus (Guerreiro et al, 2013; Jonsson et al, 2013) which affect the risk of AD previously not identified in GWAS (Giri et al, 2016; Lambert et al, 2013; Naj and Schellenberg, 2016).…”

Section: Introductionmentioning

confidence: 99%

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

Chaudhury

Patel

Barber

et al. 2018

Neurobiology of Aging

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Sporadic early-onset Alzheimer’s disease (sEOAD) exhibits the symptoms of late-onset Alzheimer’s disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer’s disease (AD) identifies APOE ε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer’s Project consortium, with association data from 17,008 late-onset Alzheimer’s disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.

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Follow-up of loci from the International Genomics of Alzheimer’s Disease Project identifies TRIP4 as a novel susceptibility gene

Cited by 86 publications

References 19 publications

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

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