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1. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Author

Spracklen, Cassandra N., Karaderi, Tugce, Yaghootkar, Hanieh, Schurmann, Claudia, Fine, Rebecca S., Kutalik, Zoltan, Preuss, Michael H., Lu, Yingchang, Wittemans, Laura B. L., Adair, Linda S., Allison, Matthew, Amin, Najaf, Auer, Paul L., Bartz, Traci M., Blueher, Matthias, Boehnke, Michael, Borja, Judith B., Bork-Jensen, Jette, Broer, Linda, Chasman, Daniel I., Chen, Yii-Der Ida, Chirstofidou, Paraskevi, Demirkan, Ayse, van Duijn, Cornelia M., Feitosa, Mary F., Garcia, Melissa E., Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Guo, Xiuqing, Haesser, Jeffrey, Hansen, Torben, Harris, Tamara B., Highland, Heather M., Hong, Jaeyoung, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Rebecca, Jousilahti, Pekka, Kahonen, Mika, Kizer, Jorge R., Kovacs, Peter, Kriebel, Jennifer, Laakso, Markku, Lange, Leslie A., Lehtimaki, Terho, Li, Jin, Li-Gao, Ruifang, Lind, Lars, Luan, Jian'an, Lyytikainen, Leo-Pekka, MacGregor, Stuart, Mackey, David A., Mahajan, Anubha, Mangino, Massimo, Mannisto, Satu, McCarthy, Mark I., McKnight, Barbara, Medina-Gomez, Carolina, Meigs, James B., Molnos, Sophie, Mook-Kanamori, Dennis, Morris, Andrew P., de Mutsert, Renee, Nalls, Mike A., Nedeljkovic, Ivana, North, Kari E., Pennell, Craig E., Pradhan, Aruna D., Province, Michael A., Raitakari, Olli T., Raulerson, Chelsea K., Reiner, Alex P., Ridker, Paul M., Ripatti, Samuli, Roberston, Neil, Rotter, Jerome I., Salomaa, Veikko, Sandoval-Zarate, America A., Sitlani, Colleen M., Spector, Tim D., Strauch, Konstantin, Stumvoll, Michael, Taylor, Kent D., Thuesen, Betina, Toenjes, Anke, Uitterlinden, Andre G., Venturini, Cristina, Walker, Mark, Wang, Carol A., Wang, Shuai, Wareham, Nicholas J., Willems, Sara M., van Dijk, Ko Willems, Wilson, James G., Wu, Ying, Yao, Jie, Young, Kristin L., Langenberg, Claudia, Frayling, Timothy M., Kilpelainen, Tuomas O., Lindgren, Cecilia M., Loos, Ruth J. F., Mohlke, Karen L., Spracklen, Cassandra N., Karaderi, Tugce, Yaghootkar, Hanieh, Schurmann, Claudia, Fine, Rebecca S., Kutalik, Zoltan, Preuss, Michael H., Lu, Yingchang, Wittemans, Laura B. L., Adair, Linda S., Allison, Matthew, Amin, Najaf, Auer, Paul L., Bartz, Traci M., Blueher, Matthias, Boehnke, Michael, Borja, Judith B., Bork-Jensen, Jette, Broer, Linda, Chasman, Daniel I., Chen, Yii-Der Ida, Chirstofidou, Paraskevi, Demirkan, Ayse, van Duijn, Cornelia M., Feitosa, Mary F., Garcia, Melissa E., Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Guo, Xiuqing, Haesser, Jeffrey, Hansen, Torben, Harris, Tamara B., Highland, Heather M., Hong, Jaeyoung, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Rebecca, Jousilahti, Pekka, Kahonen, Mika, Kizer, Jorge R., Kovacs, Peter, Kriebel, Jennifer, Laakso, Markku, Lange, Leslie A., Lehtimaki, Terho, Li, Jin, Li-Gao, Ruifang, Lind, Lars, Luan, Jian'an, Lyytikainen, Leo-Pekka, MacGregor, Stuart, Mackey, David A., Mahajan, Anubha, Mangino, Massimo, Mannisto, Satu, McCarthy, Mark I., McKnight, Barbara, Medina-Gomez, Carolina, Meigs, James B., Molnos, Sophie, Mook-Kanamori, Dennis, Morris, Andrew P., de Mutsert, Renee, Nalls, Mike A., Nedeljkovic, Ivana, North, Kari E., Pennell, Craig E., Pradhan, Aruna D., Province, Michael A., Raitakari, Olli T., Raulerson, Chelsea K., Reiner, Alex P., Ridker, Paul M., Ripatti, Samuli, Roberston, Neil, Rotter, Jerome I., Salomaa, Veikko, Sandoval-Zarate, America A., Sitlani, Colleen M., Spector, Tim D., Strauch, Konstantin, Stumvoll, Michael, Taylor, Kent D., Thuesen, Betina, Toenjes, Anke, Uitterlinden, Andre G., Venturini, Cristina, Walker, Mark, Wang, Carol A., Wang, Shuai, Wareham, Nicholas J., Willems, Sara M., van Dijk, Ko Willems, Wilson, James G., Wu, Ying, Yao, Jie, Young, Kristin L., Langenberg, Claudia, Frayling, Timothy M., Kilpelainen, Tuomas O., Lindgren, Cecilia M., Loos, Ruth J. F., and Mohlke, Karen L.

Abstract

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Published
2019
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2. Benchmarker: An Unbiased, Association-Data-Driven Strategy to Evaluate Gene Prioritization Algorithms.

Author

Fine, Rebecca S., Pers, Tune H., Amariuta, Tiffany, Raychaudhuri, Soumya, and Hirschhorn, Joel N.

Subjects
*HUMAN biology, *GENE expression, *GENES, *LINKAGE disequilibrium, *GENE mapping, *HERITABILITY
Abstract

Genome-wide association studies (GWASs) are valuable for understanding human biology, but associated loci typically contain multiple associated variants and genes. Thus, algorithms that prioritize likely causal genes and variants for a given phenotype can provide biological interpretations of association data. However, a critical, currently missing capability is to objectively compare performance of such algorithms. Typical comparisons rely on "gold standard" genes harboring causal coding variants, but such gold standards may be biased and incomplete. To address this issue, we developed Benchmarker, an unbiased, data-driven benchmarking method that compares performance of similarity-based prioritization strategies to each other (and to random chance) by leave-one-chromosome-out cross-validation with stratified linkage disequilibrium (LD) score regression. We first applied Benchmarker to 20 well-powered GWASs and compared gene prioritization based on strategies employing three different data sources, including annotated gene sets and gene expression; genes prioritized based on gene sets had higher per-SNP heritability than those prioritized based on gene expression. Additionally, in a direct comparison of three methods, DEPICT and MAGMA outperformed NetWAS. We also evaluated combinations of methods; our results indicated that combining data sources and algorithms can help prioritize higher-quality genes for follow-up. Benchmarker provides an unbiased approach to evaluate any similarity-based method that provides genome-wide prioritization of genes, variants, or gene sets and can determine the best such method for any particular GWAS. Our method addresses an important unmet need for rigorous tool assessment and can assist in mapping genetic associations to causal function. [ABSTRACT FROM AUTHOR]

Published
2019
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3. Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Author

Graff, Mariaelisa, Justice, Anne E., Young, Kristin L., Marouli, Eirini, Zhang, Xinruo, Fine, Rebecca S., Lim, Elise, Buchanan, Victoria, Rand, Kristin, Feitosa, Mary F., Wojczynski, Mary K., Yanek, Lisa R., Shao, Yaming, Rohde, Rebecca, Adeyemo, Adebowale A., Aldrich, Melinda C., Allison, Matthew A., Ambrosone, Christine B., Ambs, Stefan, and Amos, Christopher

Subjects
*GENEALOGY, *METAGENOMICS, *GENE frequency
Abstract

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3 , NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations. [ABSTRACT FROM AUTHOR]

Published
2021
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4. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Author

Spracklen CN, Karaderi T, Yaghootkar H, Schurmann C, Fine RS, Kutalik Z, Preuss MH, Lu Y, Wittemans LBL, Adair LS, Allison M, Amin N, Auer PL, Bartz TM, Blüher M, Boehnke M, Borja JB, Bork-Jensen J, Broer L, Chasman DI, Chen YI, Chirstofidou P, Demirkan A, van Duijn CM, Feitosa MF, Garcia ME, Graff M, Grallert H, Grarup N, Guo X, Haesser J, Hansen T, Harris TB, Highland HM, Hong J, Ikram MA, Ingelsson E, Jackson R, Jousilahti P, Kähönen M, Kizer JR, Kovacs P, Kriebel J, Laakso M, Lange LA, Lehtimäki T, Li J, Li-Gao R, Lind L, Luan J, Lyytikäinen LP, MacGregor S, Mackey DA, Mahajan A, Mangino M, Männistö S, McCarthy MI, McKnight B, Medina-Gomez C, Meigs JB, Molnos S, Mook-Kanamori D, Morris AP, de Mutsert R, Nalls MA, Nedeljkovic I, North KE, Pennell CE, Pradhan AD, Province MA, Raitakari OT, Raulerson CK, Reiner AP, Ridker PM, Ripatti S, Roberston N, Rotter JI, Salomaa V, Sandoval-Zárate AA, Sitlani CM, Spector TD, Strauch K, Stumvoll M, Taylor KD, Thuesen B, Tönjes A, Uitterlinden AG, Venturini C, Walker M, Wang CA, Wang S, Wareham NJ, Willems SM, Willems van Dijk K, Wilson JG, Wu Y, Yao J, Young KL, Langenberg C, Frayling TM, Kilpeläinen TO, Lindgren CM, Loos RJF, and Mohlke KL

Published
2019
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