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Papers In Press, published online ahead of print May 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800515-JLR200

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Journal of Lipid Research, Vol. 50, 798-806, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q

Carole Ober^1,*,, Alex S. Nord^,**, Emma E. Thompson^*, Lin Pan^2,*, Zheng Tan^3,*, Darren Cusanovich^*, Ying Sun^*, Raluca Nicolae^*, Celina Edelstein, Daniel H. Schneider^*, Christine Billstrand^*, Ditta Pfaffinger, Natasha Phillips^*, Rebecca L. Anderson^*, Binu Philips, Ramakrishnan Rajagopalan, Thomas S. Hatsukami^***, Mark J. Rieder^***, Patrick J. Heagerty, Deborah A. Nickerson^**, Mark Abney^*, Santica Marcovina^***, Gail P. Jarvik^,**, Angelo M. Scanu^, and Dan L. Nicolae^*,,

^* Department of Human Genetics, University of Chicago, Chicago, IL
Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL
Department of Medicine, University of Chicago, Chicago, IL
Department of Statistics, University of Chicago, Chicago, IL
Division of Medical Genetics, University of Washington Medical Center, Seattle, WA
^** Department of Genomic Sciences, University of Washington Medical Center, Seattle, WA
^*** Department of Vascular Surgery, University of Washington Medical Center, Seattle, WA
Department of Biostatistics, University of Washington Medical Center, Seattle, WA
² Present address for L. Pan: Department of Biostatistics, Emory University, 1365-B Clifton Road NE, Room B, 4112 Atlanta, GA.
³ Present address for Z. Tan: Medical Genetics Laboratories, Baylor College of Medicine, One Baylor Plaza, NAB 2015 Houston, TX 77030.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one figure and one table.

This work was supported by grants from the National Institutes of Health (R01 HL66533, R01 HL63209, P50 HL56399, and M01 RR00055) and Hoffman-LaRoche to the University of Chicago, and National Institutes of Health grants U01 HL66682, R01 HL074366, R01HL67406, P01 HL30086, and P01 HL072262 to the University of Washington.

Published, JLR Papers in Press, January 5, 2009.

¹ To whom correspondence should be addressed. e-mail: c-ober{at}genetics.uchicago.edu

Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P 1.3 x 10^–7) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P = 7.3 x 10^–12 and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.

Supplementary key words genome-wide association study • LPA • carotid artery disease • kringle IV

Abbreviations: apo(a), apolipoprotein(a); BMI, body mass index; LD, linkage disequilibrium; Lp(a), lipoprotein (a); SNP, single nucleotide polymorphism; RSS, residual sum of squares

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