@article {6068, title = {Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.}, journal = {Hum Genet}, volume = {132}, year = {2013}, month = {2013 Jan}, pages = {79-90}, abstract = {

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

}, keywords = {Adult, Ankyrins, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 14, Cohort Studies, Female, Genome-Wide Association Study, Hepatocyte Nuclear Factor 3-alpha, Humans, Linkage Disequilibrium, Lung, Male, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive}, issn = {1432-1203}, doi = {10.1007/s00439-012-1219-6}, author = {Hansel, Nadia N and Ruczinski, Ingo and Rafaels, Nicholas and Sin, Don D and Daley, Denise and Malinina, Alla and Huang, Lili and Sandford, Andrew and Murray, Tanda and Kim, Yoonhee and Vergara, Candelaria and Heckbert, Susan R and Psaty, Bruce M and Li, Guo and Elliott, W Mark and Aminuddin, Farzian and Dupuis, Jos{\'e}e and O{\textquoteright}Connor, George T and Doheny, Kimberly and Scott, Alan F and Boezen, H Marike and Postma, Dirkje S and Smolonska, Joanna and Zanen, Pieter and Mohamed Hoesein, Firdaus A and de Koning, Harry J and Crystal, Ronald G and Tanaka, Toshiko and Ferrucci, Luigi and Silverman, Edwin and Wan, Emily and Vestbo, Jorgen and Lomas, David A and Connett, John and Wise, Robert A and Neptune, Enid R and Mathias, Rasika A and Par{\'e}, Peter D and Beaty, Terri H and Barnes, Kathleen C} } @article {6991, title = {Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.}, journal = {Stroke}, volume = {47}, year = {2016}, month = {2016 Feb}, pages = {307-16}, abstract = {

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5{\texttimes}10(-6) and performed in silico association analyses in an independent sample of <=1003 cases and 7745 controls.

RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5{\texttimes}10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

}, keywords = {Adult, African Continental Ancestry Group, Age of Onset, Aged, Asian Continental Ancestry Group, Brain Ischemia, Chromosomes, Human, Pair 10, Computer Simulation, DNA, Intergenic, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Serine Endopeptidases, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.115.011328}, author = {Cheng, Yu-Ching and Stanne, Tara M and Giese, Anne-Katrin and Ho, Weang Kee and Traylor, Matthew and Amouyel, Philippe and Holliday, Elizabeth G and Malik, Rainer and Xu, Huichun and Kittner, Steven J and Cole, John W and O{\textquoteright}Connell, Jeffrey R and Danesh, John and Rasheed, Asif and Zhao, Wei and Engelter, Stefan and Grond-Ginsbach, Caspar and Kamatani, Yoichiro and Lathrop, Mark and Leys, Didier and Thijs, Vincent and Metso, Tiina M and Tatlisumak, Turgut and Pezzini, Alessandro and Parati, Eugenio A and Norrving, Bo and Bevan, Steve and Rothwell, Peter M and Sudlow, Cathie and Slowik, Agnieszka and Lindgren, Arne and Walters, Matthew R and Jannes, Jim and Shen, Jess and Crosslin, David and Doheny, Kimberly and Laurie, Cathy C and Kanse, Sandip M and Bis, Joshua C and Fornage, Myriam and Mosley, Thomas H and Hopewell, Jemma C and Strauch, Konstantin and M{\"u}ller-Nurasyid, Martina and Gieger, Christian and Waldenberger, Melanie and Peters, Annette and Meisinger, Christine and Ikram, M Arfan and Longstreth, W T and Meschia, James F and Seshadri, Sudha and Sharma, Pankaj and Worrall, Bradford and Jern, Christina and Levi, Christopher and Dichgans, Martin and Boncoraglio, Giorgio B and Markus, Hugh S and Debette, Stephanie and Rolfs, Arndt and Saleheen, Danish and Mitchell, Braxton D} }