The UCSD / O'Connor “TSP” (Twin/Sibling/Pedigree) Resource in Hypertension has been made available to honor the legacy of Dr. Daniel T. O’Connor (1948-2014). Dr. O’Connor was a faculty member in the Division of Nephrology-Hypertension at the University of California, San Diego (UCSD) for 35+ years with a diverse set of interests, all of which converged on his steadfast belief that translational studies – i.e., studies seeking to take the insights obtained from basic research and turn them in to something of use in clinical and public health contexts to improve lives – are highly interdisciplinary by nature. The resource includes data generated from many of Dr. O’Connor’s diverse and complementary studies, primarily those focused on the renovascular, cardiovascular and circulatory systems, particularly hypertension, using his long-standing study of twins and their relatives. Although details of the specific data types are provided in the relevant data sheets and links, the brief descriptions below provide insight into the nature of the data.
Example Findings: To give a flavor of the sorts of studies the resource was designed to pursue, consider that Dr. O’Connor published over 400 peer-reviewed papers, many taking advantage of different and complementary aspects of the resource. For example, Dr. O’Connor and colleagues pursued a series of studies investigating the role of proteins that package neurotransmitters in renovascular hypertension and other renal diseases. One of these proteins, Chromogranin A (CHGA), was sequenced and all potential functional variants were assessed and tested in in vitro assays, including both coding and regulatory variants [Ref 1]. This work was pursued well before efficient WGS technologies were available, and resulted in fundamental insights into the role of CHGA variation in molecular physiologic processes of relevance to blood pressure regulation. Dr. O’Connor and colleagues considered the products of CHGA and identified Catestatin, a proteolytic product of CHGA, as a regulator of blood pressure in a series of laboratory studies [Ref 2]. Dr. O’Connor and colleagues then went on to identify additional genetic variants associated with CHGA and related proteins and peptides in humans using association study methodologies [Ref 3] as well as additional clinical correlates [Refs 4, 5]. Ultimately, Catestatin and congeners are currently in development for clinical use in a wide variety of contexts and would not have received the attention they are getting but for Dr. O’Connor and colleague’s multidisciplinary studies, enabled, in part, by the available data and resources described here.
Study Design & Demographics: This “TSP” Resource contains N=697 (215 male and 482 female) participants. At the time of recruitment individuals ranged from 15-84 years of age and had varying ethnic backgrounds (Whites, African-Americans and Hispanics). The cohort was developed to study the genetic basis of autonomic dysfunction in human essential hypertension (reviewed in Zhang et al. Curr Hypertens Rep. 2011 13: 36-45) and contains cross-sectionally collected phenotypes related to blood pressure regulation.
The following was written by Dr. O’Connor in 2011
Significance. With the advent of the post-genomic era, clinical investigators in every discipline and subspecialty now require access to genomic DNA from well-phenotyped individuals, in both healthy (control) and disease groups. Furthermore, the extent of phenotyping must be broad (covering the expertise across disciplines), deep (sufficiently sophisticated to enhance or maximize the value of associated genetic information), and longitudinal (to allow genetic information to predict practical clinical outcomes or end points). To this end, we are offering the UCSD twin project as a genomic and phenotypic resource.
Why twins? Human twin pairs represent a variety of advantageous properties for post-genomic medicine study design. First of all, when ascertained simply on the basis of membership in a twin-ship, twins provide, in a very literal sense, a random (relatively unbiased) sample of the population. Second, twins provide a unique window into the relative roles of heredity and environment in determination of any trait (phenotype), including disease traits, by decomposition into variance (SD2) components. Simply put, the population variance (SD2) of any trait or phenotype (VP) is the additive sum of its genetic (VG) and environmental (VE) components, as follows: VP=VG+VE. Heritability (h2) is the fraction of VP accounted for by VG: h2=VG/VP. In turn, h2 can be estimated from trait correlations in MZ versus DZ pairs, as follows: h2= VG/VP =2(RMZ-RDZ). The simplicity and power of the human twin method are apparent. h2 provides an immediate index of the tractability of any trait to genetic analysis.
Twins and “risk” (or susceptibility) traits or alleles. Currently healthy individuals typically harbor numerous risk traits for future disease. This approach is especially well worked out for cardiovascular disease, and risk of hypertension, atherosclerosis, myocardial infarction, stroke, and congestive heart failure. Twins allow partitioning of such risk traits into genetic versus environmental components. We have used the twin method to probe such risk traits as BP, C-reactive protein, lipids, hemodynamic stress responses, catecholamine secretion, and hepatic transaminase release.
Gene-by-environment interactions. The twin method can be used to quantify interactions between genetic loci and environmental perturbations, such as estimating dependence of cardiovascular (BP, HR) responses to environmental stress on genetic variants at either candidate loci, or genome-wide.
1. Wen G, Mahata SK, Cadman P, Mahata M, Ghosh S, Mahapatra NR, Rao F, Stridsberg M, Smith DW, Mahboubi P, Schork NJ, O'Connor DT, Hamilton BA. Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology. Am J Hum Genet. 2004 Feb;74(2):197-207. doi: 10.1086/381399. Epub 2004 Jan 12. PMID: 14740315.
2.Mahata SK, Mahata M, Fung MM, O'Connor DT. Catestatin: a multifunctional peptide from chromogranin A. Regul Pept. 2010 Jun 8;162(1-3):33-43. doi: 10.1016/j.regpep.2010.01.006. Epub 2010 Jan 28. PMID: 20116404.
3.Benyamin B, Maihofer AX, Schork AJ, Hamilton BA, Rao F, Schmid-Schönbein GW, Zhang K, Mahata M, Stridsberg M, Schork NJ, Biswas N, Hook VY, Wei Z, Montgomery GW, Martin NG, Nievergelt CM, Whitfield JB, O'Connor DT. Identification of novel loci affecting circulating chromogranins and related peptides. Hum Mol Genet. 2017 Jan 1;26(1):233-242. doi: 10.1093/hmg/ddw380. PMID: 28011710
4. Rao F, Chiron S, Wei Z, Fung MM, Chen Y, Wen G, Khandrika S, Ziegler MG, Benyamin B, Montgomery G, Whitfield JB, Martin NG, Waalen J, Hamilton BA, Mahata SK, O'Connor DT. Genetic variation within a metabolic motif in the chromogranin a promoter: pleiotropic influence on cardiometabolic risk traits in twins. Am J Hypertens. 2012 Jan;25(1):29-40. doi: 10.1038/ajh.2011.163. Epub 2011 Sep 15. PMID: 21918574 Free PMC article.
5.Chen Y, Rao F, Wen G, Gayen JR, Zhang K, Vaingankar SM, Biswas N, Mahata M, Friese RS, Fung MM, Salem RM, Nievergelt C, Bhatnagar V, Hook VY, Ziegler MG, Mahata SK, Hamilton BA, O'Connor DT. Naturally occurring genetic variants in human chromogranin A (CHGA) associated with hypertension as well as hypertensive renal disease. Cell Mol Neurobiol. 2010 Nov;30(8):1395-400. doi: 10.1007/s10571-010-9600-2. PMID: 2106116