@article {1303, title = {Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002138}, abstract = {

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92\%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48\%, 61\%, and 57\%), American Indians (45\%, 64\%, and 77\%), and Mexican Americans/Hispanics (57\%, 56\%, and 86\%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Continental Population Groups, Female, Gene Frequency, Genetics, Population, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Lipid Metabolism, Lipoproteins, HDL, Lipoproteins, LDL, Male, Middle Aged, Molecular Epidemiology, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Triglycerides, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002138}, author = {Dumitrescu, Logan and Carty, Cara L and Taylor, Kira and Schumacher, Fredrick R and Hindorff, Lucia A and Ambite, Jos{\'e} L and Anderson, Garnet and Best, Lyle G and Brown-Gentry, Kristin and B{\r u}zkov{\'a}, Petra and Carlson, Christopher S and Cochran, Barbara and Cole, Shelley A and Devereux, Richard B and Duggan, Dave and Eaton, Charles B and Fornage, Myriam and Franceschini, Nora and Haessler, Jeff and Howard, Barbara V and Johnson, Karen C and Laston, Sandra and Kolonel, Laurence N and Lee, Elisa T and MacCluer, Jean W and Manolio, Teri A and Pendergrass, Sarah A and Quibrera, Miguel and Shohet, Ralph V and Wilkens, Lynne R and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Buyske, Steven and Kooperberg, Charles and North, Kari E and Crawford, Dana C} } @article {1311, title = {Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jul}, pages = {e1002193}, abstract = {

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10$^{-}$$^{6}$$^{4}$) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10$^{-}$$^{5}$$^{8}$) and docosapentaenoic acid (DPA, p = 4 x 10$^{-}${\textonesuperior}$^{5}$$^{4}$). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10$^{-}${\textonesuperior}{\texttwosuperior}) and DPA (p = 1 x 10$^{-}$$^{4}${\textthreesuperior}) and lower docosahexaenoic acid (DHA, p = 1 x 10$^{-}${\textonesuperior}$^{5}$). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10$^{-}$$^{8}$). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

}, keywords = {Alleles, Continental Population Groups, Fatty Acids, Omega-3, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002193}, author = {Lemaitre, Rozenn N and Tanaka, Toshiko and Tang, Weihong and Manichaikul, Ani and Foy, Millennia and Kabagambe, Edmond K and Nettleton, Jennifer A and King, Irena B and Weng, Lu-Chen and Bhattacharya, Sayanti and Bandinelli, Stefania and Bis, Joshua C and Rich, Stephen S and Jacobs, David R and Cherubini, Antonio and McKnight, Barbara and Liang, Shuang and Gu, Xiangjun and Rice, Kenneth and Laurie, Cathy C and Lumley, Thomas and Browning, Brian L and Psaty, Bruce M and Chen, Yii-der I and Friedlander, Yechiel and Djouss{\'e}, Luc and Wu, Jason H Y and Siscovick, David S and Uitterlinden, Andr{\'e} G and Arnett, Donna K and Ferrucci, Luigi and Fornage, Myriam and Tsai, Michael Y and Mozaffarian, Dariush and Steffen, Lyn M} } @article {6067, title = {Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e68095}, abstract = {

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77\% were concordant, 0.14\% had missing data, and 0.09\% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.

}, keywords = {Aging, Alleles, Cluster Analysis, Cohort Studies, Continental Population Groups, Exome, Female, Gene Frequency, Genomics, Genotype, Heart, Humans, Male, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Sample Size, Self Report, Sequence Analysis, DNA}, issn = {1932-6203}, doi = {10.1371/journal.pone.0068095}, author = {Grove, Megan L and Yu, Bing and Cochran, Barbara J and Haritunians, Talin and Bis, Joshua C and Taylor, Kent D and Hansen, Mark and Borecki, Ingrid B and Cupples, L Adrienne and Fornage, Myriam and Gudnason, Vilmundur and Harris, Tamara B and Kathiresan, Sekar and Kraaij, Robert and Launer, Lenore J and Levy, Daniel and Liu, Yongmei and Mosley, Thomas and Peloso, Gina M and Psaty, Bruce M and Rich, Stephen S and Rivadeneira, Fernando and Siscovick, David S and Smith, Albert V and Uitterlinden, Andre and van Duijn, Cornelia M and Wilson, James G and O{\textquoteright}Donnell, Christopher J and Rotter, Jerome I and Boerwinkle, Eric} } @article {6683, title = {Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.}, journal = {Circ Cardiovasc Genet}, volume = {8}, year = {2015}, month = {2015 Apr}, pages = {398-409}, abstract = {

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7{\texttimes}10(-19)) and identified novel loci on chr10q24 (P=1.6{\texttimes}10(-9)) and chr2p21 (P=4.4{\texttimes}10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0{\texttimes}10(-8)) and chr2p16 (P=1.5{\texttimes}10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

}, keywords = {Aged, Aged, 80 and over, Chromosomes, Human, Continental Population Groups, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Models, Genetic, Stroke, White Matter}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.114.000858}, author = {Verhaaren, Benjamin F J and Debette, Stephanie and Bis, Joshua C and Smith, Jennifer A and Ikram, M Kamran and Adams, Hieab H and Beecham, Ashley H and Rajan, Kumar B and Lopez, Lorna M and Barral, Sandra and van Buchem, Mark A and van der Grond, Jeroen and Smith, Albert V and Hegenscheid, Katrin and Aggarwal, Neelum T and de Andrade, Mariza and Atkinson, Elizabeth J and Beekman, Marian and Beiser, Alexa S and Blanton, Susan H and Boerwinkle, Eric and Brickman, Adam M and Bryan, R Nick and Chauhan, Ganesh and Chen, Christopher P L H and Chouraki, Vincent and de Craen, Anton J M and Crivello, Fabrice and Deary, Ian J and Deelen, Joris and De Jager, Philip L and Dufouil, Carole and Elkind, Mitchell S V and Evans, Denis A and Freudenberger, Paul and Gottesman, Rebecca F and Gu{\dh}nason, Vilmundur and Habes, Mohamad and Heckbert, Susan R and Heiss, Gerardo and Hilal, Saima and Hofer, Edith and Hofman, Albert and Ibrahim-Verbaas, Carla A and Knopman, David S and Lewis, Cora E and Liao, Jiemin and Liewald, David C M and Luciano, Michelle and van der Lugt, Aad and Martinez, Oliver O and Mayeux, Richard and Mazoyer, Bernard and Nalls, Mike and Nauck, Matthias and Niessen, Wiro J and Oostra, Ben A and Psaty, Bruce M and Rice, Kenneth M and Rotter, Jerome I and von Sarnowski, Bettina and Schmidt, Helena and Schreiner, Pamela J and Schuur, Maaike and Sidney, Stephen S and Sigurdsson, Sigurdur and Slagboom, P Eline and Stott, David J M and van Swieten, John C and Teumer, Alexander and T{\"o}glhofer, Anna Maria and Traylor, Matthew and Trompet, Stella and Turner, Stephen T and Tzourio, Christophe and Uh, Hae-Won and Uitterlinden, Andr{\'e} G and Vernooij, Meike W and Wang, Jing J and Wong, Tien Y and Wardlaw, Joanna M and Windham, B Gwen and Wittfeld, Katharina and Wolf, Christiane and Wright, Clinton B and Yang, Qiong and Zhao, Wei and Zijdenbos, Alex and Jukema, J Wouter and Sacco, Ralph L and Kardia, Sharon L R and Amouyel, Philippe and Mosley, Thomas H and Longstreth, W T and DeCarli, Charles C and van Duijn, Cornelia M and Schmidt, Reinhold and Launer, Lenore J and Grabe, Hans J and Seshadri, Sudha S and Ikram, M Arfan and Fornage, Myriam} }