Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin

被引：15

作者：

Toenjes, Anke ^{[1
]}

Scholz, Markus ^{[2
,3
]}

Krueger, Jacqueline ^{[4
]}

Krause, Kerstin ^{[1
]}

Schleinitz, Dorit ^{[1
]}

Kirsten, Holger ^{[2
,3
]}

Gebhardt, Claudia ^{[1
]}

Marzi, Carola ^{[5
,6
,7
]}

Grallert, Harald ^{[5
,6
,7
]}

Ladenvall, Claes ^{[8
,9
]}

Heyne, Henrike ^{[10
]}

Laurila, Esa ^{[8
,9
]}

Kriebel, Jennifer ^{[5
,6
,7
]}

Meisinger, Christa ^{[6
,7
]}

Rathmann, Wolfgang ^{[11
]}

Gieger, Christian ^{[5
]}

Groop, Leif ^{[8
,9
]}

Prokopenko, Inga ^{[12
,13
,14
]}

Isomaa, Bo ^{[15
,16
]}

Beutner, Frank ^{[17
]}

Kratzsch, Juergen ^{[17
]}

Fischer-Rosinsky, Antje ^{[18
]}

Pfeiffer, Andreas ^{[18
,19
]}

Krohn, Knut ^{[20
]}

Spranger, Joachim ^{[18
]}

Thiery, Joachim

Blueher, Matthias ^{[1
,4
]}

Stumvoll, Michael ^{[1
,4
]}

Kovacs, Peter ^{[4
]}

机构：

[1] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany

[2] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany

[3] Univ Leipzig, LIFE Res Ctr, D-04103 Leipzig, Germany

[4] Univ Leipzig, IFB AdiposityDis, Med Ctr, D-04103 Leipzig, Germany

[5] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany

[6] Helmholtz Ctr Munich, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany

[7] German Ctr Diabet Res DZD eV, D-85764 Neuherberg, Germany

[8] Lund Univ, Dept Clin Sci Diabet & Endocrinol, S-20502 Malmo, Sweden

[9] Lund Univ, CRC, Skane Univ Hosp, Diabet Ctr, S-20502 Malmo, Sweden

[10] Univ Leipzig, Inst Human Genet, D-04103 Leipzig, Germany

[11] Heinrich Heine Univ Dusseldorf, Leibniz Ctr Diabet Res, Inst Biometr & Epidemiol, German Diabet Ctr, D-40225 Dusseldorf, Germany

[12] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[13] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England

[14] Imperial Coll London, Dept Genom Common Dis, London SW7 2AZ, England

[15] Dept Social Serv & Healthcare, Pietarsaari 68601, Finland

[16] Folkhalsan Res Ctr, Helsinki 00290, Finland

[17] Univ Hosp Leipzig, Inst Lab Med Clin Chem & Mol Diagnost, D-04103 Leipzig, Germany

[18] Charite Univ Med Berlin, Dept Endocrinol Diabet & Nutr, D-10117 Berlin, Germany

[19] German Inst Human Nutr, Dept Clin Nutr, D-14558 Nuthetal, Germany

[20] Univ Leipzig, Interdisciplinary Ctr Clin Res, D-04103 Leipzig, Germany

来源：

HUMAN MOLECULAR GENETICS | 2018年 / 27卷 / 03期

基金：

瑞典研究理事会;

关键词：

FRONTOTEMPORAL LOBAR DEGENERATION; ASSOCIATION ANALYSIS; INSULIN-RESISTANCE; ADIPOSE-TISSUE; GROWTH-FACTOR; TRANS-EQTLS; EXPRESSION; PLASMA; LOCI; DDA3;

D O I：

10.1093/hmg/ddx413

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N - 848) and KORA (N - 1628) from Germany and PPP-Botnia (N - 335) from Finland (total N - 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 x 10(-50)), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 x 10(-21)). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.

引用

页码：546 / 558

页数：13

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