The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression

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The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression. / Ali, Mina; Ajore, Ram; Wihlborg, Anna Karin; Niroula, Abhishek; Swaminathan, Bhairavi; Johnsson, Ellinor; Stephens, Owen W.; Morgan, Gareth; Meissner, Tobias; Turesson, Ingemar; Goldschmidt, Hartmut; Mellqvist, Ulf Henrik; Gullberg, Urban; Hansson, Markus; Hemminki, Kari; Nahi, Hareth; Waage, Anders; Weinhold, Niels; Nilsson, Björn.

In: Nature Communications, Vol. 9, No. 1, 1649, 01.12.2018.

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Ali, Mina ; Ajore, Ram ; Wihlborg, Anna Karin ; Niroula, Abhishek ; Swaminathan, Bhairavi ; Johnsson, Ellinor ; Stephens, Owen W. ; Morgan, Gareth ; Meissner, Tobias ; Turesson, Ingemar ; Goldschmidt, Hartmut ; Mellqvist, Ulf Henrik ; Gullberg, Urban ; Hansson, Markus ; Hemminki, Kari ; Nahi, Hareth ; Waage, Anders ; Weinhold, Niels ; Nilsson, Björn. / The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression. In: Nature Communications. 2018 ; Vol. 9, No. 1.

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TY - JOUR

T1 - The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression

AU - Ali, Mina

AU - Ajore, Ram

AU - Wihlborg, Anna Karin

AU - Niroula, Abhishek

AU - Swaminathan, Bhairavi

AU - Johnsson, Ellinor

AU - Stephens, Owen W.

AU - Morgan, Gareth

AU - Meissner, Tobias

AU - Turesson, Ingemar

AU - Goldschmidt, Hartmut

AU - Mellqvist, Ulf Henrik

AU - Gullberg, Urban

AU - Hansson, Markus

AU - Hemminki, Kari

AU - Nahi, Hareth

AU - Waage, Anders

AU - Weinhold, Niels

AU - Nilsson, Björn

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P combined = 2.5 × 10-27; β combined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.

AB - Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P combined = 2.5 × 10-27; β combined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.

U2 - 10.1038/s41467-018-04082-2

DO - 10.1038/s41467-018-04082-2

M3 - Article

C2 - 29695719

AN - SCOPUS:85046094111

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1649

ER -