Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies

Abstract

Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks’ gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

“…We also constructed a GRS based on 5 SNPs (GRS 5 ) associated with fasting glucose in pregnancy (rs560887, rs6235, rs1260326, rs7936247 and rs4841132). 23 GRS 5 explained about 6.6% of fasting glucose variance. Finally, we constructed another GRS with all glycemic SNPs genotyped (GRS 21 ).…”

“…[22][23][24][25] To build our first IV, we selected 10 of these SNPs to construct our genetic risk score (GRS 10 ) representing maternal glucose levels based on the variance explained (each SNP r 2 0.002 in association with maternal fasting glucose in Gen3G). We observed that a higher GRS 10 was associated with higher maternal fasting glucose at 2nd trimester and found that the moderate association was highly significant by statistical testing (b G1 D 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE D 0.007; P D 7.76 £ 10 ¡11 ; N D 467; Fig.…”

“…The GRS 10 explained 8.7% of maternal fasting glucose variance (r-square). We also tested GRS that were more inclusive (built on the 21 SNPs; r 2 D 4.6%; P D 2.96 £ 10 ¡6 ) or more parsimonious (5 SNPs previously associated with fasting glucose specifically in pregnancy 23 ; r 2 D 6.6%; P D 1.57 £ 10 ¡8 ), but we selected GRS 10 as our primary IV as it explained the largest variance in maternal fasting glucose. Moreover, our IV GRS 10 was considered a valid representative of maternal fasting glucose for MR based on a technique developed by Kang.…”

“…We had initially selected and genotyped a total of 21 SNPs related to fasting glucose in literature essentially published by MAGIC, 22,24,25 including variants that were shown to be associated with glycemic traits during pregnancy. 23 In Table S1, we present information on these 21 SNPs including nearest reported gene, risk allele (raising fasting glucose), frequency of the risk allele in our dataset and effect size on fasting glucose in our cohort of pregnant women. We selected 10 SNPs with the largest effect (r 2 0.002; see Table S1) on fasting glucose and consistent, expected direction of effect.…”

Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection

“…Notably, variants in G6PC2 have been consistently associated with FG levels, whereas their contribution to T2D risk remains controversial. In particular, the rs560887 SNP is one of the strongest signals associated to FG (and related traits), and one of the most commonly replicated in large-scale analyses [3][4][5][6][52][53][54]. Moreover, the variant was shown to be functional and to modulate G6PC2 pre-mRNA splicing [7].…”