T2D-GENES: San Antonio Mexican American Family Studies (SAMAFS)

The Type 2 Diabetes (T2D) Genetic Exploration by Next-generation sequencing in Ethnic Samples (T2D-GENES) Consortium is a collaborative international effort to identify genes influencing susceptibility to type 2 diabetes in multiple ethnic groups using next generation sequencing. To fulfill this objective, T2D-GENES Consortium undertook two large sequencing studies, called T2D-GENES Projects 1 and 2. Project 1 has carried out whole exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 non-diabetic controls, equally divided among five continental ancestry groups: Europeans, East Asians, South Asians, Hispanic Americans, and African Americans. The goal of Project 1 is to identify all genetic variants in the complete coding regions of the genomes (i.e., whole exome) by sequencing, including rare variants. Project 2 (i.e., SAMAFS substudy 2) is a pedigree-based study designed to identify low frequency or rare variants influencing susceptibility to T2D, using whole genome sequence information from approximately 600 individuals in 20 Mexican American T2D-enriched pedigrees from San Antonio, Texas, augmented with family-based imputation into approximately 440 additional family members. The major objectives of Project 2 are to identify low frequency or rare variants in and around known common variant signals for T2D, as well as to find novel low frequency or rare variants influencing susceptibility to T2D. Both T2D-GENES Projects 1 and 2 involve the San Antonio Mexican American Family Studies (SAMAFS), which are composed of four San Antonio, Texas-based family studies: the San Antonio Family Heart Study (SAFHS), San Antonio Family Diabetes/Gallbladder Study (SAFDGS), Veterans Administration Genetic Epidemiology Study (VAGES), and Family Investigation of Nephropathy and Diabetes - San Antonio (FIND-SA) Component and its extension called the Extended FIND [E-FIND]. The SAFHS and SAFDGS began in 1991 and have followed participants with extensive clinical phenotyping related to T2D for over 20 years. The VAGES was initiated in 1994 and a large battery of T2D-related phenotypic data has been obtained from its participants. The FIND-SA began in 2000, a part of the multicenter FIND study which was designed to identify genetic determinants of diabetic kidney disease; data from its participants related to T2D were used for this project. Non-overlapping subsets of SAMAFS participants are part of the T2D-GENES Projects 1 and 2, henceforth referred to as SAMAFS substudies 1 and 2, respectively. The SAMAFS substudies 1 and 2 are part of one of the five awards funded by NIDDK under a cooperative agreement award mechanism, which is governed by the Steering Committee of the T2D-GENES Consortium. Since Project 1 relies on population based subsets of cases and controls, 491 unrelated participants are drawn from the four SAMAFS as part of the T2D-GENES Project 1 Mexican American sample (i.e., SAMAFS substudy 1). The whole exome sequencing was performed at the Broad Institute. For Project 2, 1048 individuals are drawn from two SAMAFS (SAFHS and SAFDGS), representing 20 large families for substudy 2. The substudy 2 strategy is to sequence approximately 600 individuals at an average of 50x coverage across the entire genome, then impute genome wide genotypes for about 440 additional family members. The 600 sequenced individuals are specifically chosen for their value in imputing sequence information into other family members. By studying large pedigrees, we expect to find multiple individuals carrying each genetic variant, even if this variant is very rare in the population at large. Thus, a pedigree-based approach provides an excellent opportunity for identifying rare novel variants influencing risk of T2D and quantitative variation in T2D-related phenotypes. The whole genome sequencing has been done commercially by Complete Genomics, Inc. (CGI). The available sample of 1,048 includes 5 sequenced individuals who do not belong to any of the 20 large pedigrees. The final family data of 1,043 individuals includes whole genome sequence data for 607 individuals. After quality control, 590 sequenced individuals provide data for family based imputation using Merlin linkage analysis software into approximately 440 additional family members for whom chip based genotypes are available to indicate which parental haplotype is transmitted. The complete SAMAFS data including phenotype, genotype, sequence, other T2D-related trait data utilized for Projects 1 and 2 are available. These data can readily be viewed by clicking on the substudy title shown below or in the box: "Substudies", located on the right hand side of this parent or top study page phs000847.v1.p1, titled T2D-GENES Consortium: San Antonio Mexican American Family Studies (SAMAFS). phs000849 T2D-GENES Project 1: San Antonio Mexican American Family Studies (SAMAFS), Substudy 1: Whole Exome Sequencing phs000462 T2D-GENES Project 2: San Antonio Mexican American Family Studies (SAMAFS), Substudy 2: Whole Genome Sequencing in Pedigrees]]>
The San Antonio Mexican American Family Studies (SAMAFS) are composed of four San Antonio-based family studies: the San Antonio Family Heart Study (SAFHS), San Antonio Family Diabetes/Gallbladder Study (SAFDGS), Veterans Administration Genetic Epidemiology Study (VAGES), and Family Investigation of Nephropathy and Diabetes - San Antonio (FIND-SA) Component and its extension called the Extended FIND [E-FIND]. These family studies have been conducted in San Antonio, Texas, representing the Mexican American population. The SAFHS began in 1991, and included 1,431 individuals in 42 extended families at baseline. Probands were 40 to 60 year old low-income Mexican Americans selected at random without regard to presence or absence of disease, almost exclusively from Mexican American census tracts in San Antonio, Texas. All first, second and third degree relatives of the proband and of the proband's spouse, aged 16 years or above, were eligible to participate in the study. As part of our ongoing studies, we are currently recruiting new family members from the original families. The SAFDGS also began in 1991, and originally included 579 examined individuals distributed across 32 pedigrees as part of the San Antonio Family Diabetes Study (SAFDS). The sample size was expanded to 40 families and more than 900 individuals through two recalls. The second recall refers to the San Antonio Family Gallbladder Study (SAFGS), which recruited new family members from the original SAFDS families and family members from 8 newly recruited families. The probands for the SAFDGS were individuals with T2D identified in an earlier epidemiologic survey, the San Antonio Heart Study. Only low-income Mexican Americans identified in the San Antonio Heart study as having T2D were eligible to be probands. These individuals were approached in random order without regard to how many T2D individuals were in their families (i.e., no attempt was made to preferentially recruit multiplex families). Thus, the T2D probands in the SAFDGS constitute a population based case series of T2D individuals. All first, second and third degree relatives, aged 18 or above, were invited to participate in the study. As part of our ongoing studies, we have recalled some SAFDGS participants. The VAGES began in 1994, and originally included 1,122 participants from 307 families for whom the T2D status was known. These families were ascertained on at least 2 siblings affected with T2D and one parent with T2D. Inclusion criteria required the presence of at least 5 first-degree relatives per family including the affected sib pair and both parents, and the recruited family members were aged 18 years or above. In later years, new family members from the original VAGES families were recruited to expand the sample size to more than 1,500 individuals; and, a few of the VAGES participants were recalled once or twice as part of other studies. The FIND-SA family study is a part of the FIND consortium, which represents 11 clinical centers and multi-ethnic populations including Mexican Americans. Its major objective was to examine genetic factors that influence susceptibility to diabetic nephropathy. Its data were obtained from individuals with T2D ascertained for diabetic nephropathy and their first-degree relatives, mostly siblings; and, data from a few nondiabetic individuals were also collected. The FIND-SA recruitment began in 2000; and 1,240 individuals were enrolled. Additionally, in 2005, the Extended FIND (E-FIND) study, expanded 50 families that were already enrolled at the San Antonio FIND center by recruiting relatives of first, second and third generations (N = 320). These 1,560 (1240 + 320) individuals, aged 18 years or above, were distributed across 243 families.]]>
The T2D-GENES Consortium's San Antonio component is part of one of the five awards funded by NIDDK under a cooperative agreement award mechanism. The T2D-GENES Consortium was established by NIDDK in 2009 and has been governed by the Steering Committee of the T2D-GENES Consortium. Its major objective was to identify susceptibility loci for T2D with an emphasis on US minority populations disproportionately affected by T2D. To fulfill its objective, two major sequencing projects have come into existence: Projects 1 and 2. The Project 1 (Whole Exome Sequencing) aimed to assess contribution of exonic (protein coding) variation to susceptibility to T2D using data from five major ethnic/ancestry groups: Europeans, East Asians, South Asians, Hispanic Americans, and African Americans. Each of these five groups was composed of ~1,000 T2D cases and ~1,000 non-T2D controls. As part of the Mexican American data and to supplement the Hispanic data from the Starr County Study (Texas), data/samples from 490 unrelated individuals from SAMAFS (i.e., SAFHS, SAFDGS, VAGES, and FIND-SA) were utilized (SAMAFS substudy 1). The Project 2's (Whole Genome Sequencing) objective was to identify low frequency or rare variants in the complete genetic regions of the genomes (i.e., whole genome) influencing susceptibility to T2D, including rare variants that segregate within families. Of the SAMAFS families representing the SAFHS and SAFDGS (SAMAFS substudy 2), 20 large pedigrees, consisting of 1,043 individuals, were selected for this project by focusing on large lineages in order to maximize the number of founder copies as well as to get an optimal ratio of sequencing efficiency and sufficient number of T2D individuals. These pedigrees average approximately 52 individuals with a maximum pedigree size of 87 individuals. To select individuals for whole genome sequencing, the program "ExomePicks" was used, which suggests informative family members to be sequenced from large pedigrees. In total, approximately 600 individuals were chosen for WGS. The full sequences for the remaining of the 1,043 individuals are obtained using family-based imputation, given that individuals in the sample are previously assessed for a high-density SNP framework. The individuals of Project 2 (SAFHS and SAFDGS) have been followed in a mixed longitudinal fashion, up to a maximum of 5 visits. Phenotype data, including T2D affection status and T2D-related quantitative traits (e.g., glucose, insulin, BMI, blood pressure, and lipids), are available for the study participants. The genome-wide genotype data, representing more than one million SNPs based on different versions of the Illumina Infinium Beadchips, are available for the study participants. The raw genotype data obtained were processed using standard quality control procedures. Phenotype data, including T2D affection status and T2D-related quantitative traits are also available for VAGES, and a few of the VAGES participants were recalled once or twice as part of other studies. For FIND-SA, T2D affection status related data are available, which are cross-sectional in nature.]]>