A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

AESG; Daniela Hartl; Patrick May; Wei Gu; Manuel Mayhaus; Sabrina Pichler; Christian Spaniol; Enrico Glaab; Dheeraj Reddy Bobbili; Paul Antony; Sandra Koegelsberger; Alexander Kurz; Timo Grimmer; Kevin Morgan; Badri N. Vardarajan; Christiane Reitz; John Hardy; Jose Bras; Rita Guerreiro; Rudi Balling; Jochen G. Schneider; Matthias Riemenschneider; Celeste Sassi; J. Raphael Gibbs; Dena Hernandez; Keeley J. Brookes; Tamar Guetta-Baranes; Paul T. Francis; Michelle K. Lupton; Kristelle Brown; John Powell; Andrew Singleton

doi:10.1038/s41380-018-0091-8

A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

AESG, Daniela Hartl^*, Patrick May, Wei Gu, Manuel Mayhaus, Sabrina Pichler, Christian Spaniol, Enrico Glaab, Dheeraj Reddy Bobbili, Paul Antony, Sandra Koegelsberger, Alexander Kurz, Timo Grimmer, Kevin Morgan, Badri N. Vardarajan, Christiane Reitz, John Hardy, Jose Bras, Rita Guerreiro, Rudi BallingJochen G. Schneider, Matthias Riemenschneider, Celeste Sassi, J. Raphael Gibbs, Dena Hernandez, Keeley J. Brookes, Tamar Guetta-Baranes, Paul T. Francis, Michelle K. Lupton, Kristelle Brown, John Powell, Andrew Singleton

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aβ formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.

Original language	English
Number of pages	11
Journal	Molecular Psychiatry
DOIs	https://doi.org/10.1038/s41380-018-0091-8
Publication status	Published - 9 Jul 2018

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AESG, Hartl, D., May, P., Gu, W., Mayhaus, M., Pichler, S., Spaniol, C., Glaab, E., Bobbili, D. R., Antony, P., Koegelsberger, S., Kurz, A., Grimmer, T., Morgan, K., Vardarajan, B. N., Reitz, C., Hardy, J., Bras, J., Guerreiro, R., ... Singleton, A. (2018). A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease. Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0091-8

@article{7c883e4ff3e247ea9c26163e599c12d8,

title = "A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease",

abstract = "Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aβ formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.",

author = "AESG and Daniela Hartl and Patrick May and Wei Gu and Manuel Mayhaus and Sabrina Pichler and Christian Spaniol and Enrico Glaab and Bobbili, {Dheeraj Reddy} and Paul Antony and Sandra Koegelsberger and Alexander Kurz and Timo Grimmer and Kevin Morgan and Vardarajan, {Badri N.} and Christiane Reitz and John Hardy and Jose Bras and Rita Guerreiro and Rudi Balling and Schneider, {Jochen G.} and Matthias Riemenschneider and Celeste Sassi and Gibbs, {J. Raphael} and Dena Hernandez and Brookes, {Keeley J.} and Tamar Guetta-Baranes and Francis, {Paul T.} and Lupton, {Michelle K.} and Kristelle Brown and John Powell and Andrew Singleton",

year = "2018",

month = jul,

day = "9",

doi = "10.1038/s41380-018-0091-8",

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

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AESG, Hartl, D, May, P, Gu, W, Mayhaus, M, Pichler, S, Spaniol, C, Glaab, E, Bobbili, DR, Antony, P, Koegelsberger, S, Kurz, A, Grimmer, T, Morgan, K, Vardarajan, BN, Reitz, C, Hardy, J, Bras, J, Guerreiro, R, Balling, R, Schneider, JG, Riemenschneider, M, Sassi, C, Gibbs, JR, Hernandez, D, Brookes, KJ, Guetta-Baranes, T, Francis, PT, Lupton, MK, Brown, K, Powell, J & Singleton, A 2018, 'A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease', Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0091-8

TY - JOUR

T1 - A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

AU - AESG

AU - Hartl, Daniela

AU - May, Patrick

AU - Gu, Wei

AU - Mayhaus, Manuel

AU - Pichler, Sabrina

AU - Spaniol, Christian

AU - Glaab, Enrico

AU - Bobbili, Dheeraj Reddy

AU - Antony, Paul

AU - Koegelsberger, Sandra

AU - Kurz, Alexander

AU - Grimmer, Timo

AU - Morgan, Kevin

AU - Vardarajan, Badri N.

AU - Reitz, Christiane

AU - Hardy, John

AU - Bras, Jose

AU - Guerreiro, Rita

AU - Balling, Rudi

AU - Schneider, Jochen G.

AU - Riemenschneider, Matthias

AU - Sassi, Celeste

AU - Gibbs, J. Raphael

AU - Hernandez, Dena

AU - Brookes, Keeley J.

AU - Guetta-Baranes, Tamar

AU - Francis, Paul T.

AU - Lupton, Michelle K.

AU - Brown, Kristelle

AU - Powell, John

AU - Singleton, Andrew

PY - 2018/7/9

Y1 - 2018/7/9

N2 - Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aβ formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.

AB - Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aβ formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.

UR - http://www.scopus.com/inward/record.url?scp=85049613267&partnerID=8YFLogxK

U2 - 10.1038/s41380-018-0091-8

DO - 10.1038/s41380-018-0091-8

M3 - Article

AN - SCOPUS:85049613267

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

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