Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

Jakobsdóttir, Jóhanna; Lee, Sven J. van der; Bis, Joshua C.; Chouraki, Vincent; Li‐Kroeger, David; Yamamoto, Shinya; Grove, Megan L.; Naj, Adam C.; Vronskaya, Maria; Salazar, Jose L.; DeStefano, Anita L.; Brody, Jennifer A.; Smith, Albert V.; Amin, Najaf; Sims, Rebecca; Ibrahim-Verbaas, Carla A.; Choi, Seung Hoan; Satizabal, Claudia L.; López, Oscar L.; Beiser, Alexa; Ikram, M. Arfan; García, Melissa; Hayward, Caroline; Varga, Tibor V.; Ripatti, Samuli; Franks, Paul W.; Hallmans, Göran; Rolandsson, Olov; Jansson, Jan Håkon; Porteous, David J.; Salomaa, Veikko; Eiríksdóttir, Guðný; Rice, Kenneth; Bellen, Hugo J.; Levy, Daniel; Uitterlinden, André G.; Emilsson, Valur; Rotter, Jerome I.; Aspelund, Thor; O’Donnell, Christopher J.; Fitzpatrick, Annette L.; Launer, Lenore J.; Hofman, Albert; Wang, Li San; Williams, Julie; Schellenberg, Gerard D.; Boerwinkle, Eric; Psaty, Bruce M.; Seshadri, Sudha; Liu, Zhandong; Gudnason, Vilmundur; Duijn, Cornelia M. van

doi:10.1371/journal.pgen.1006327

Cited by 51 publications

(69 citation statements)

References 57 publications

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“…Other than the well-established coding variants (p.C112R and p.R158C) in APOE (APOlipoprotein E , OMIM #104310)[431–433], however, the significance of most of these variants awaits to be experimentally verified. Through a recent exome-wide association study, the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium[434,435] identified a rare coding variant in a previously uncharacterized gene that has a strong effect size on LOAD[436]. A P155L variant in TM2D3 (TM2 domain containing 3) was associated with a ~7.5 fold chance of developing LOAD and a 10-year earlier age of onset in an Icelandic population.…”

Section: Using Drosophila To Study Rare Functional Variants In Genes mentioning

confidence: 99%

“…Since the variant amino acid (p.P155) is not conserved between human and Drosophila , we humanized the fly amx gene by generating a genomic rescue construct in which the fly amx coding region has been replaced by the human sequence. Interestingly, the reference TM2D3 was able to partially rescue the neurogenic phenotype and lethality of the maternal amx mutant embryos, whereas TM2D3 with the p.P155L variant was not able to do so[436]. Hence, p.P155L associated with LOAD was shown to be a functional variant based on Notch-signaling related phenotypic assay performed in vivo , and further functional studies are ongoing to determine the precise molecular function of TM2D3/Amx in vivo .…”

Section: Using Drosophila To Study Rare Functional Variants In Genes mentioning

confidence: 99%

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Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

Salazar

Yamamoto

2018

Advances in Experimental Medicine and Biology

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Notch signaling research dates back to more than one hundred years, beginning with the identification of the Notch mutant in the fruit fly Drosophila melanogaster. Since then, research on Notch and related genes in flies has laid the foundation of what we now know as the Notch signaling pathway. In the 1990s, basic biological and biochemical studies of Notch signaling components in mammalian systems, as well as identification of rare mutations in Notch signaling pathway genes in human patients with rare Mendelian diseases or cancer, increased the significance of this pathway in human biology and medicine. In the 21st century, Drosophila and other genetic model organisms continue to play a leading role in understanding basic Notch biology. Furthermore, these model organisms can be used in a translational manner to study underlying mechanisms of Notch-related human diseases and to investigate the function of novel disease associated genes and variants. In this chapter, we first briefly review the major contributions of Drosophila to Notch signaling research, discussing the similarities and differences between the fly and human pathways. Next, we introduce several biological contexts in Drosophila in which Notch signaling has been extensively characterized. Finally, we discuss a number of genetic diseases caused by mutations in genes in the Notch signaling pathway in humans and we expand on how Drosophila can be used to study rare genetic variants associated with these and novel disorders. By combining modern genomics and state-of-the art technologies, Drosophila research is continuing to reveal exciting biology that sheds light onto mechanisms of disease.

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Section: Using Drosophila To Study Rare Functional Variants In Genes mentioning

confidence: 99%

Section: Using Drosophila To Study Rare Functional Variants In Genes mentioning

confidence: 99%

Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

Salazar

Yamamoto

2018

Advances in Experimental Medicine and Biology

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“…Sequencing in a multiply-affected family found a rare, missense variant in TTC3 that was shared in all affected members of the family [64]. A rare variant in the gene TM2D3 was enriched in Icelanders with LOAD and identified as a functionally damaging allele [65]. Two variants in tight linkage disequilibrium in AKAP9 were found to be associated with LOAD in African Americans [66].…”

Section: Gwasmentioning

confidence: 99%

Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

Raghavan

Tosto

2017

Curr Neurol Neurosci Rep

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Purpose of Review We aimed to summarize the recent advances in genetic findings of Alzheimer’s disease (AD), focusing on traditional single-marker and gene approaches and non-traditional ones, i.e., polygenic and epistatic components. Recent Findings Genetic studies have progressed over the last few decades from linkage to genome-wide association studies (GWAS), and most recently studies utilizing high-throughput sequencing. So far, GWASs have identified several common variants characterized by small effect sizes (besides APOE-ε4). Sequencing has facilitated the study of rare variants with larger effects. Nevertheless, missing heritability for AD remains extensive; a possible explanation might lie in the existence of polygenic and epistatic components. Summary We review findings achieved by single-marker approaches, but also polygenic and epistatic associations. The latter two are critical, yet-underexplored mechanisms. Genes involved in complex diseases are likely regulated by mechanisms and pathways involving many other genes, an aspect potentially missed by traditional approaches.

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“…For example, the functional impact of a rare TM2D3 human variant that was predicted to be non-pathogenic was identified in association with late onset AD susceptibility [64]. The loss of the fly homologue of TM2D3 , almondex ( amx ), is known to cause embryonic lethality and severe neurogenic defects.…”

Section: Introductionmentioning

confidence: 99%

Genetic strategies to tackle neurological diseases in fruit flies

Şentürk

Bellen

2018

Current Opinion in Neurobiology

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Drosophila melanogaster is a genetic model organism that has contributed to the discovery of numerous genes whose human homologues are associated with diseases. The development of sophisticated genetic tools to manipulate its genome accelerates the discovery of the genetic basis of undiagnosed human diseases and the elucidation of molecular pathogenic events of known and novel diseases. Here, we discuss various approaches used in flies to assess the function of the fly homologues of disease-associated genes. We highlight how systematic and combinatorial approaches based on recently established methods provide us with integrated tool sets that can be applied to the study of neurodevelopmental and neurodegenerative disorders.

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Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

Cited by 51 publications

References 57 publications

Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

Genetic strategies to tackle neurological diseases in fruit flies

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