This paper from the De Strooper lab convincingly shows that there is not a clear effect of PLD3 on APP biology and reignites the debate on whether PLD3 is an AD gene (Cruchaga et al., 2013).
Genetic analysis looking for rare variants is subject to difficult confounds. Usually, cases and controls are collected in subtly different ways and they may not be perfectly matched. In the U.K., for example, a higher proportion of controls were collected from the Cambridge area. These subtle population differences don’t cause a problem in GWAs with genes with modest effect sizes, but as studies look for GWAs hits of very small effect sizes or at rare variants like PLD3, these small population stratification issues can cause problems. For example, a founder variant in the Cambridge area could be mistaken for a protective allele in this sample. In the case of PLD3, replication attempts have given mixed results with no clear outcome (van der Lee et al., 2015; Lambert et al., 2015; Heilmann et al., 2015; Hooli et al., 2015). One hopes that a clear outcome on PLD3 will come from the massive sequencing efforts both in the U.S. and in Europe. PLD3 is not alone in remaining in pathogenic limbo. Since TREM2 was reported, no other new genes have yet been consistently replicated. In contrast, rare variants found in GWAs hits seem to give more consistent results.
Replication of genetic associations, outside of the first study, remains the most effective mechanism for deciding what is correct.
References:
Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, Norton J, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M, UK Brain Expression Consortium, Hardy J, Ryten M, Trabzuni D, Weale ME, Ramasamy A, Smith C, Sassi C, Bras J, Gibbs JR, Hernandez DG, Lupton MK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, Munger RG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K, Alzheimer’s Research UK Consortium, Passmore P, Craig D, Johnston J, McGuinness B, Todd S, Heun R, Kölsch H, Kehoe PG, Hooper NM, Vardy ER, Mann DM, Pickering-Brown S, Brown K, Kalsheker N, Lowe J, Morgan K, David Smith A, Wilcock G, Warden D, Holmes C, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton AB, Hardy J, Kamboh MI, St George-Hyslop P, Cairns N, Morris JC, Kauwe JS, Goate AM.
Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.
Nature. 2014 Jan 23;505(7484):550-4. Epub 2013 Dec 11
PubMed.
van der Lee SJ, Holstege H, Wong TH, Jakobsdottir J, Bis JC, Chouraki V, van Rooij JG, Grove ML, Smith AV, Amin N, Choi SH, Beiser AS, Garcia ME, van IJcken WF, Pijnenburg YA, Louwersheimer E, Brouwer RW, van den Hout MC, Oole E, Eirkisdottir G, Levy D, Rotter JI, Emilsson V, O'Donnell CJ, Aspelund T, Uitterlinden AG, Launer LJ, Hofman A, Boerwinkle E, Psaty BM, DeStefano AL, Scheltens P, Seshadri S, van Swieten JC, Gudnason V, van der Flier WM, Ikram MA, van Duijn CM.
PLD3 variants in population studies.
Nature. 2015 Apr 2;520(7545):E2-3.
PubMed.
Heilmann S, Drichel D, Clarimon J, Fernández V, Lacour A, Wagner H, Thelen M, Hernández I, Fortea J, Alegret M, Blesa R, Mauleón A, Roca MR, Kornhuber J, Peters O, Heun R, Frölich L, Hüll M, Heneka MT, Rüther E, Riedel-Heller S, Scherer M, Wiltfang J, Jessen F, Becker T, Tárraga L, Boada M, Maier W, Lleó A, Ruiz A, Nöthen MM, Ramirez A.
PLD3 in non-familial Alzheimer's disease.
Nature. 2015 Apr 2;520(7545):E3-5.
PubMed.
Hooli BV, Lill CM, Mullin K, Qiao D, Lange C, Bertram L, Tanzi RE.
PLD3 gene variants and Alzheimer's disease.
Nature. 2015 Apr 2;520(7545):E7-8.
PubMed.
Comments
Institute of Neurology, UCL
This paper from the De Strooper lab convincingly shows that there is not a clear effect of PLD3 on APP biology and reignites the debate on whether PLD3 is an AD gene (Cruchaga et al., 2013).
Genetic analysis looking for rare variants is subject to difficult confounds. Usually, cases and controls are collected in subtly different ways and they may not be perfectly matched. In the U.K., for example, a higher proportion of controls were collected from the Cambridge area. These subtle population differences don’t cause a problem in GWAs with genes with modest effect sizes, but as studies look for GWAs hits of very small effect sizes or at rare variants like PLD3, these small population stratification issues can cause problems. For example, a founder variant in the Cambridge area could be mistaken for a protective allele in this sample. In the case of PLD3, replication attempts have given mixed results with no clear outcome (van der Lee et al., 2015; Lambert et al., 2015; Heilmann et al., 2015; Hooli et al., 2015). One hopes that a clear outcome on PLD3 will come from the massive sequencing efforts both in the U.S. and in Europe. PLD3 is not alone in remaining in pathogenic limbo. Since TREM2 was reported, no other new genes have yet been consistently replicated. In contrast, rare variants found in GWAs hits seem to give more consistent results.
Replication of genetic associations, outside of the first study, remains the most effective mechanism for deciding what is correct.
References:
Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, Norton J, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M, UK Brain Expression Consortium, Hardy J, Ryten M, Trabzuni D, Weale ME, Ramasamy A, Smith C, Sassi C, Bras J, Gibbs JR, Hernandez DG, Lupton MK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, Munger RG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K, Alzheimer’s Research UK Consortium, Passmore P, Craig D, Johnston J, McGuinness B, Todd S, Heun R, Kölsch H, Kehoe PG, Hooper NM, Vardy ER, Mann DM, Pickering-Brown S, Brown K, Kalsheker N, Lowe J, Morgan K, David Smith A, Wilcock G, Warden D, Holmes C, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton AB, Hardy J, Kamboh MI, St George-Hyslop P, Cairns N, Morris JC, Kauwe JS, Goate AM. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature. 2014 Jan 23;505(7484):550-4. Epub 2013 Dec 11 PubMed.
van der Lee SJ, Holstege H, Wong TH, Jakobsdottir J, Bis JC, Chouraki V, van Rooij JG, Grove ML, Smith AV, Amin N, Choi SH, Beiser AS, Garcia ME, van IJcken WF, Pijnenburg YA, Louwersheimer E, Brouwer RW, van den Hout MC, Oole E, Eirkisdottir G, Levy D, Rotter JI, Emilsson V, O'Donnell CJ, Aspelund T, Uitterlinden AG, Launer LJ, Hofman A, Boerwinkle E, Psaty BM, DeStefano AL, Scheltens P, Seshadri S, van Swieten JC, Gudnason V, van der Flier WM, Ikram MA, van Duijn CM. PLD3 variants in population studies. Nature. 2015 Apr 2;520(7545):E2-3. PubMed.
Lambert JC, Grenier-Boley B, Bellenguez C, Pasquier F, Campion D, Dartigues JF, Berr C, Tzourio C, Amouyel P. PLD3 and sporadic Alzheimer's disease risk. Nature. 2015 Apr 2;520(7545):E1. PubMed.
Heilmann S, Drichel D, Clarimon J, Fernández V, Lacour A, Wagner H, Thelen M, Hernández I, Fortea J, Alegret M, Blesa R, Mauleón A, Roca MR, Kornhuber J, Peters O, Heun R, Frölich L, Hüll M, Heneka MT, Rüther E, Riedel-Heller S, Scherer M, Wiltfang J, Jessen F, Becker T, Tárraga L, Boada M, Maier W, Lleó A, Ruiz A, Nöthen MM, Ramirez A. PLD3 in non-familial Alzheimer's disease. Nature. 2015 Apr 2;520(7545):E3-5. PubMed.
Hooli BV, Lill CM, Mullin K, Qiao D, Lange C, Bertram L, Tanzi RE. PLD3 gene variants and Alzheimer's disease. Nature. 2015 Apr 2;520(7545):E7-8. PubMed.
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