Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation

被引：203

作者：

Galarneau, Genevieve ^{[2
]}

Palmer, Cameron D. ^{[3
,4
,5
,6
]}

Sankaran, Vijay G. ^{[1
,7
]}

Orkin, Stuart H. ^{[1
,7
,8
]}

Hirschhorn, Joel N. ^{[3
,4
,5
,6
,9
]}

Lettre, Guillaume ^{[2
,10
]}

机构：

[1] Childrens Hosp Boston, Div Hematol & Oncol, Boston, MA 02115 USA

[2] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[3] Childrens Hosp Boston, Div Genet, Boston, MA USA

[4] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA

[5] Childrens Hosp Boston, Program Genom, Boston, MA USA

[6] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[7] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[8] Howard Hughes Med Inst, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[10] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada

来源：

NATURE GENETICS | 2010年 / 42卷 / 12期

关键词：

GENOME-WIDE ASSOCIATION; EXPRESSION; HBS1L-MYB; VARIANTS; BCL11A;

D O I：

10.1038/ng.707

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We used resequencing and genotyping in African Americans with sickle cell anemia (SCA) to characterize associations with fetal hemoglobin (HbF) levels at the BCL11A, HBS1L-MYB and beta-globin loci. Fine-mapping of HbF association signals at these loci confirmed seven SNPs with independent effects and increased the explained heritable variation in HbF levels from 38.6% to 49.5%. We also identified rare missense variants that causally implicate MYB in HbF production.

引用

页码：1049 / 1051

页数：3

共 15 条

[1] Rare Variants Create Synthetic Genome-Wide Associations [J].

Dickson, Samuel P. ;

Wang, Kai ;

Krantz, Ian ;

Hakonarson, Hakon ;

Goldstein, David B. .

PLOS BIOLOGY, 2010, 8 (01)

[2]

Embury S.H., 1994, SICKLE CELL DIS BASI

[3] Amelioration of Sardinian β0 thalassemia by genetic modifiers [J].

Galanello, Renzo ;

Sanna, Serena ;

Perseu, Lucia ;

Sollaino, Maria Carla ;

Satta, Stefania ;

Lai, Maria Eliana ;

Barella, Susanna ;

Uda, Manuela ;

Usala, Gianluca ;

Abecasis, Goncalo R. ;

Cao, Antonio .

BLOOD, 2009, 114 (18) :3935-3937

[4] COMMON HAPLOTYPE DEPENDENCY OF HIGH-G-GAMMA-GLOBIN GENE-EXPRESSION AND HIGH HB F-LEVELS IN BETA-THALASSEMIA AND SICKLE-CELL ANEMIA PATIENTS [J].

LABIE, D ;

PAGNIER, J ;

LAPOUMEROULIE, C ;

ROUABHI, F ;

DUNDABELKHODJA, O ;

CHARDIN, P ;

BELDJORD, C ;

WAJCMAN, H ;

FABRY, ME ;

NAGEL, RL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1985, 82 (07) :2111-2114

[5] DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease [J].

Lettre, Guillaume ;

Sankaran, Vijay G. ;

Bezerra, Marcos Andre C. ;

Araujo, Aderson S. ;

Uda, Manuela ;

Sanna, Serena ;

Cao, Antonio ;

Schlessinger, David ;

Costa, Fernando F. ;

Hirschhorn, Joel N. ;

Orkin, Stuart H. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (33) :11869-11874

[6] Finding the missing heritability of complex diseases [J].

Manolio, Teri A. ;

Collins, Francis S. ;

Cox, Nancy J. ;

Goldstein, David B. ;

Hindorff, Lucia A. ;

Hunter, David J. ;

McCarthy, Mark I. ;

Ramos, Erin M. ;

Cardon, Lon R. ;

Chakravarti, Aravinda ;

Cho, Judy H. ;

Guttmacher, Alan E. ;

Kong, Augustine ;

Kruglyak, Leonid ;

Mardis, Elaine ;

Rotimi, Charles N. ;

Slatkin, Montgomery ;

Valle, David ;

Whittemore, Alice S. ;

Boehnke, Michael ;

Clark, Andrew G. ;

Eichler, Evan E. ;

Gibson, Greg ;

Haines, Jonathan L. ;

Mackay, Trudy F. C. ;

McCarroll, Steven A. ;

Visscher, Peter M. .

NATURE, 2009, 461 (7265) :747-753

[7] A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15 [J].

Menzel, Stephan ;

Garner, Chad ;

Gut, Ivo ;

Matsuda, Fumihiko ;

Yamaguchi, Masao ;

Heath, Simon ;

Foglio, Mario ;

Zelenika, Diana ;

Boland, Anne ;

Rooks, Helen ;

Best, Steve ;

Spector, Tim D. ;

Farrall, Martin ;

Lathrop, Mark ;

Thein, Swee Lay .

NATURE GENETICS, 2007, 39 (10) :1197-1199

[8] Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes [J].

Nejentsev, Sergey ;

Walker, Neil ;

Riches, David ;

Egholm, Michael ;

Todd, John A. .

SCIENCE, 2009, 324 (5925) :387-389

[9] A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E [J].

Nuinoon, Manit ;

Makarasara, Wattanan ;

Mushiroda, Taisei ;

Setianingsih, Iswari ;

Wahidiyat, Pustika Amalia ;

Sripichai, Orapan ;

Kumasaka, Natsuhiko ;

Takahashi, Atsushi ;

Svasti, Saovaros ;

Munkongdee, Thongperm ;

Mahasirimongkol, Surakameth ;

Peerapittayamongkol, Chayanon ;

Viprakasit, Vip ;

Kamatani, Naoyuki ;

Winichagoon, Pranee ;

Kubo, Michiaki ;

Nakamura, Yusuke ;

Fucharoen, Suthat .

HUMAN GENETICS, 2010, 127 (03) :303-314

[10] Heritability of cardiovascular and personality traits in 6,148 sardinians [J].

Pilia, Giuseppe ;

Chen, Wei-Min ;

Scuteri, Angelo ;

Orru, Marco ;

Albai, Giuseppe ;

Dei, Mariano ;

Lai, Sandra ;

Usala, Gianluca ;

Lai, Monica ;

Loi, Paola ;

Mameli, Cinzia ;

Vacca, Loredana ;

Deiana, Manila ;

Olla, Nazario ;

Masala, Marco ;

Cao, Antonio ;

Najjar, Samer S. ;

Terracciano, Antonio ;

Nedorezov, Timur ;

Sharov, Alexei ;

Zonderman, Alan B. ;

Abecasis, Goncalo R. ;

Costa, Paul ;

Lakatta, Edward ;

Schlessinger, David .

PLOS GENETICS, 2006, 2 (08) :1207-1223

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