Sophia Gaynor and Xue Xiao Present at Genetics Student Seminar 11/14/16
Targeted Sequencing and Functional Assessment of the 2p25 Region in Suicide Attempters with Bipolar Disorder
Sophia C. Gaynor1, Marie E. Breen1, Eric T. Monson1, Kelly de Klerk1, Meredith Parsons1, Peter P. Zandi2, James B. Potash1, Virginia L. Willour1
1 Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
2 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
We previously conducted a genome-wide association study (GWAS) of the attempted suicide phenotype. This GWAS implicated common variation in the 2p25 region, a 350kb region encompassing four genes (FAM110C, SH3YL1, ACP1, FAM150B). The top 2p25 signals were exclusively in intergenic regions and were largely driven by males. In the current study, we have conducted a targeted next-generation sequencing study of the entire 2p25 region in 476 bipolar suicide attempters (224 males and 252 females) and 473 bipolar non-attempters (222 males and 251 females) in an attempt to identify both common and rare variants that may contribute to the risk for suicidal behavior. Our top gene-level result from this study was FAM150B (p = 0.022), but this result did not survive correction for multiple testing. Our top individual variant from this study was rs300799, an intergenic variant between FAM110C and SH3YL1. This variant was significantly associated with the attempted suicide phenotype in male subjects, with the minor allele present in 22.3% of attempters and 12.3% of non-attempters (p = 4.84 x 10-5, corrected p = 0.035, odds ratio = 2.13). Nearly all of our top individual-variant results from sequencing fell within an 80kb linkage disequilibrium (LD) block in 2p25. Because this 80kb LD block is entirely intergenic, we performed a functional assessment of this region using the CRISPR-Cas genome-editing tool to identify any potential regulatory elements. This functional assessment revealed nominally increased expression of FAM110C (fold change = 1.39, p = 0.084) and FAM150B (fold change = 1.77, p = 0.082) following deletion of a segment of this 80kb region. This study provides further support for a putative role of the 2p25 region in the attempted suicide phenotype.
USING MAXGEL TO STUDY COMPLEMENT REGULATION BY FH FAMILY PROTEINS IN EXTRACELLULAR MATRIX
Xue Xiao1,2, Yuzhou Zhang2, Richard JH Smith1,2
1 Interdepartmental PhD Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
2Molecular Otolaryngology and Renal Research Laboratories, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Complement FH family proteins are important regulators of complement system. They are coded by CFH and CFHRs genes located on chromosome 1. Mutations in this region can cause C3 glomerulopathy (C3G). Although deletion in CFHR3-1 is not uncommon in European American population, this genetic change is associated with C3G occurrence. Recent studies came up with the hypothesis that FHRs and FH can compete with each other in regulating complement activity on cell surface. While there is currently no existing suitable system that can be used to study complement regulation on cell surface and it is still unclear how this competition happens. By using MaxGel to mimic the extracellular matrix structure on glomerular basement membrane, we were able to study the complement regulation on cell surface and to reveal the regulation of complement FH family proteins. In this study, we found that complement components, like C3 and FH can bind to MaxGel. By incubating C3b, FB, FD together, C3 convertase formed on MaxGel and the C3 convertase formation was regulated by complement regulators. FH is a negative regulator in complement system; its concentration influenced C3 convertase formation. We also found that FH binding to M axGel was reduced in some C3G patients, especially in patients with CFHR3-1 copy number changes. This study used a new system to mimic the environment on glomerular basement membrane and illustrate the role of factor H related proteins in the control of complement activity.