SEARCH for Diabetes in Youth Study - Genetic Risk Score

Genetic risk scores (GRS) quantify polygenic disease risk into a single measure and can aid in disease classification. GRS studies have focused primarily on adult populations of recent European ancestry. We aimed to assess the utility of GRS in classification of diabetes type among racially/ethnically diverse youth in the United States. We used data from SEARCH baseline visits and follow up visits for which key data elements were available. 2260 participants are included. Phenotypic Data to be submitted here include: Self-reported sex, race and ethnicity Diabetes type determined by provider Etiologic diabetes type T1D (antibody positive, or antibody negative/missing and insulin sensitive) T2D (antibody negative and insulin resistant) Diabetes duration (years) Age at diagnosis (years) Measures from baseline, SEARCH 3 (follow-up) and SEARCH 4 (follow-up): Age Height Weight Waist circumference HbA1c Fasting/non-fasting glucose C-peptide Triglycerides HDL LDL Systolic Blood Pressure Diastolic Blood Pressure Measures from SEARCH 3 and 4:Arterial stiffness as characterized by PWVRetinopathy Measures from SEARCH 4 only: LV structure and diastolic function measurements from echocardiogram GAD autoantibody IAD autoantibody ZnT8 autoantibody We performed genotyping using the Illumina Multi-Ethnic Global Array (MEGA) array with 1,697,069 genotyped variants including 748,291 with minor allele frequency <0.01. Genotyping and preliminary quality control checks were performed at the Colorado Center for Personalized Medicine. After additional quality control, 2,238 samples and 900,743 variants remained for analyses. Samples genotyped on the MEGA array were categorized using SEARCH etiologic type and consisted of predominantly type 1 diabetes cases (n=2,051) but also those with other diabetes (n=133 type 2 diabetes, n=52 other diabetes including monogenic diabetes; genetic confirmation with either a genetic clinical test or test performed as an ancillary study to SEARCH). The median reported age at DNA collection was 11.2 years (interquartile range 7.6 – 14.1) with a minimum age of 1.9 years and maximum of 21.9 years. We used additional data genotyped on the Affymetrix 500K imputation scaffold chip with 239,279 genotyped variants. This cohort consisted of predominantly type 2 diabetes cases (n=417) but also those with type 1 (n=104), and other diabetes types (n=16). After additional quality control, 537 samples and 235,967 variants remained. The median reported age at collection was 11.2 years (quartile range 8.1 – 14.2) with a minimum of 2.0 years and a maximum of 21.1 years. About 100 type 2 diabetes cases were also genotyped using the MEGA chip to ensure concordance between the data sets and facilitate strand alignment between the two chips before genotypic imputation. The data sets had n=230,228 genotyped variants in common and concordance between the genotypes was high (mean correlation r2 for SNPs used in GRS=0.95). We used the 1000 Genomes reference panel to impute each data set separately, resulting in a total of 34.5M and 27.8M well-imputed variants (r2>0.8) for the MEGA and Affymetrix data sets respectively. We combined high quality imputed variants for analysis. ]]>
Inclusion criteria for these analyses were participation in the SEARCH study and the availability of DNA for generation of SNP array data, as well as measures that SEARCH has used to define diabetes etiologic type (diabetes autoantibodies, lipid profile, HbA1C) and C-peptide leve. The parent SEARCH study included 5 clinical sites: 4 geographic-based sites located in Ohio (8 counties including Cincinnati), the state of Colorado, Washington (5 counties including Seattle), the state of South Carolina and a health plan site in California (enrollees in one plan from 7 counties). The SEARCH Cohort Study is a longitudinal study of selected incident cohorts from the SEARCH Registry study. Incident cohorts of youth from 2002-2006, 2008 and 2012 were asked to participate in a baseline research visit where history, demographics, health-care related variables, clinical information and factors essential for the etiologic classification of diabetes type (diabetes related-autoantibodies and markers of insulin sensitivity) were collected near diagnosis. Participants were asked to return at 1, 2, and 5 years from baseline for repeated measures (funding cycles 1 and 2). With the start of the third funding cycle, subjects who had participated in a baseline visit, with at least 5 years duration, were included. For the initial two phases of SEARCH, participants were eligible if: Diagnosed with diabetes Less than 20 years of age Resident of defined geographic region (geographic centers) or member of defined insurance organization (health plan centers) For the third phase of the SEARCH Study (SEARCH 3), participants were eligible if: Diagnosed in 2002-2005, 2006, 2008 Previously completed a visit in SEARCH Minimum of five years since diabetes diagnosis Did not have a SEARCH visit within the previous two years For the final phase of the SEARCH Study (SEARCH 4), the following inclusion criteria were applied: All SEARCH 3 participants with T2D All SEARCH 3 minority youth participants with T1D Random sample of 1400 of the approximately 2000 non-Hispanic white youth with T1D (from SEARCH 3 with the goal of obtaining 700 visits) All participants had to be: > 10 years of age Have at least three years since SEARCH 3 visit Have at least five years of duration of diabetes Have participated in a SEARCH 3 visit ]]>