1701-P: Genome-Wide Association Study Identifies Novel Potential Associations with Birth Weight in a Southwestern American Indian Population

Epidemiologic studies in many populations have shown that birth weight is associated with risk of type 2 diabetes (T2D) in adulthood. In a Southwestern American Indian population, lower and higher birth weight groups are at higher risk for T2D than those with normal birth weight. We performed a genome-wide association study (GWAS) of birth weight in 3700 Southwestern American Indians (2037 female; 1663 male).

496,190 SNPs (allele frequency>1%) were directly genotyped using an Axiom array designed to capture common variation in this community (Affymetrix; Santa Clara, CA). Birth weight was ascertained from Arizona state and medical records. T2D was determined according to American Diabetes Association criteria at a research exam or during clinical care. Birth weight data were normalized separately by sex and analyzed for genetic associations using a mixed model (SOLAR-Eclipse; Catonsville, MD) accounting for genetic relationships (based on genetic markers among all pairs of individuals) and adjusted for birth year and the 1^st 5 genetic principal components.

We identified 41 variants suggestively associated (p<0.0001) with birth weight. The strongest associations are with rs4799141 in PARD6G (β=-0.14 SD per T allele; p=7.5E-6), rs17333221 in MEOX2 (β=-0.15 SD per C allele; p=1.0E-5), rs11704996 in TRIOBP (β=0.15 SD per A allele; p=1.0E-5) and a missense variant in ABCC8, R1420H (β=0.41 SD per H allele; p=1.5E-5).

5 of the 41 variants are also nominally associated with T2D (p<0.05) in 7659 individuals from this population; the most notable was the R1420H variant in ABCC8, which we previously reported as associated with T2D (OR=2.2, p=3.0E-5) and for which activating mutations cause hyperinsulinemic hypoglycemia of infancy. In sum, we identified novel suggestive genetic associations with birth weight, which require confirmation in additional studies, and show that R1420H in ABCC8 is a strong genetic determinant of birth weight in this population.