Genome-Wide Association Study Identifies Candidate Loci Associated with Platelet Count in Koreans

Platelets are derived from the fragments that are formed from the cytoplasm of bone marrow megakaryocytes-small irregularly shaped anuclear cells. Platelets respond to vascular damage, contracts blood vessels, and attaches to the damaged region, thereby stopping bleeding, together with the action of blood coagulation factors. Platelet activation is known to affect genes associated with vascular risk factors, as well as with arteriosclerosis and myocardial infarction. Here, we performed a genome-wide association study with 352,228 single-nucleotide polymorphisms typed in 8,842 subjects of the Korea Association Resource (KARE) project and replicated the results in 7,861 subjects from an independent population. We identified genetic associations between platelet count and common variants nearby chromosome 4p16.1 (p = 1.46 x 10(-10), in the KIAA0232 gene), 6p21 (p = 1.36 x 10(-7), in the BAK1 gene), and 12q24.12 (p = 1.11 x 10(-15), in the SH2B3 gene). Our results illustrate the value of large-scale discovery and a focus for several novel research avenues.

Genome-wide Survey of Copy Number Variants Associated with Blood Pressure and Body Mass Index in a Korean Population

Hypertension is the major factor of most death and high blood pressure (BP) can lead to stroke, myocardial infarction and cardiac failure. Moreover, hypertension is strongly correlated with body mass index (BMI). Although the exact causes of hypertension are still unclear, some of genetic loci were discovered from genome-wide association study (GWAS). Therefore, it is essential to study genetic variation for finding more genetic factor affecting hypertension. The purpose of our study is to conduct a CNV association study for hypertension-related traits, BP and BMI, in Korean individuals. We identified 2,206 CNV regions from 3,274 community-based Korean participants using the Affymetrix Genome-Wide Human SNP Array 6.0 platform and performed a logistic regression analysis of CNVs with two hypertension-related traits, BP and BMI. Moreover, the 4,692 participants in an independent cohort were selected for respective replication analyses. GWAS of CNV identified two loci encompassing previously known hypertension-related genes: LPA (lipoprotein) on 6q26, and JAK2 (Janus kinase 2) on 9p24, with suggestive p-values (0.0334 for LPA and 0.0305 for JAK2). These two positive findings, however, were not evaluated in the replication stage. Our result confirmed the conclusion of CNV study from the WTCCC suggesting weak association with common diseases. This is the first study of CNV association study with BP and BMI in Korean population and it provides a state of CNV association study with common human diseases using SNP array.

Identification of Causal and/or Rare Genetic Variants for Complex Traits by Targeted Resequencing in Population-based Cohorts

Genome-wide association studies (GWASs) have greatly contributed to the identification of common variants responsible for numerous complex traits. There are, however, unavoidable limitations in detecting causal and/or rare variants for traits in this approach, which depends on an LD-based tagging SNP microarray chip. In an effort to detect potential casual and/or rare variants for complex traits, such as type 2 diabetes (T2D) and triglycerides (TGs), we conducted a targeted resequencing of loci identified by the Korea Association REsource (KARE) GWAS. The target regions for resequencing comprised whole exons, exon-intron boundaries, and regulatory regions of genes that appeared within 1 Mb of the GWA signal boundary. From 124 individuals selected in population-based cohorts, a total of 0.7 Mb target regions were captured by the NimbleGen sequence capture 385K array. Subsequent sequencing, carried out by the Roche 454 Genome Sequencer FLX, generated about 110,000 sequence reads per individual. Mapping of sequence reads to the human reference genome was performed using the SSAHA2 program. An average of 62.2% of total reads was mapped to targets with an average 22X-fold coverage. A total of 5,983 SNPs (average 846 SNPs per individual) were called and annotated by GATK software, with 96.5% accuracy that was estimated by comparison with Affymetrix 5.0 genotyped data in identical individuals. About 51% of total SNPs were singletons that can be considered possible rare variants in the population. Among SNPs that appeared in exons, which occupies about 20% of total SNPs, 304 nonsynonymous singletons were tested with Polyphen to predict the protein damage caused by mutation. In total, we were able to detect 9 and 6 potentially functional rare SNPs for T2D and triglycerides, respectively, evoking a further step of replication genotyping in independent populations to prove their bona fide relevance to traits.