1. Background:

In the previous study, we analyzed all SNPs from Intron 1 to Intron 3 of the FTO gene to identify SNPs that exhibit a Parent-of-Origin(POE) effect on offspring BMI, depending on whether the SNP is inherited from the mother or the father. We conducted a haplotype analysis by grouping SNPs that are highly correlated in Linkage Disequilibrium (LD). The first allele of each genotype were concatenated to form the paternal haplotype, and the second allele were merged into the maternal haplotype. Then performed separate haplotype analyses for both the paternal and maternal haplotypes. The SNP with the highest minor allele frequency (MAF) from each haplotype group was selected to compare the effects of paternal and maternal inheritance. Subsequently, the heterozygous genotypes were analyzed using a linear regression model.

2. Focus on Phased Genotypes:

The results indicate that several SNPs exhibit parental origin effects (POE). Initially, we assumed that all individuals had paternal genotypes, meaning we believed that the first allele came from the father and the second from the mother, a premise applied universally to all individuals. While this assumption held true for individuals with genotype data from one or both parents, it did not apply to those lacking parental genotype information. Relying on genotype data without complete parental information may lead to potential issues. As a result, we re-evaluated the dataset. Out of 8,432 individuals, we found that only 4,403 had genotype information from one or both parents. To ensure the accuracy and reliability of our analysis, we focused on these 4,403 individuals for haplotype analysis and parental inheritance contrast. We also repeated the paternal and maternal analyses, along with the contrast analysis, specifically targeting 10 SNPs of interest among these individuals. Ultimately, we identified several SNPs that exhibited POE.

3. Hypothsis:

We assumed that additional SNPs from Intron_1 to Intron_3 will show POE on offspring BMI, and the POE is the same across the intron regardless of the SNPs, the maternal alleles always show stronger effect, or vice versa. This analysis only focused on individuals in the Framingham cohort whose parental genotype data was available from both or either parent.

4. Results

The forest plot displayed the paternal and maternal estimated coefficients with CI for the haplotype group that shows POE, along with the representative SNP within the group.

Intron_1: Among the four SNPs indicating POE in the phased individuals, two SNPs (rs12447107 and rs28711250) both demonstrates stronger but negative paternal effects. Another SNP (rs12447481) showed stronger but negative maternal effects, while one SNP (rs8047587) showed stronger positive maternal effects.

Intron_2: One SNP (rs75547181) exhibited a POE with stronger but negative paternal effects.

Intron_3: A SNP (rs16952577) indicated stronger positive maternal effects. This SNP, along with the two POE SNPs from the Trios cohort (rs17818902, rs17818920), belongs to the same haplotype group, all reflecting stronger maternal inheritance effects.

5. Comparison

The table below presents the results of haplotype analysis and single SNP analysis from the Framingham cohort, along with POE SNPs results from the Sorbs and German Trios cohorts:

Note: You may find duplicate FHS_Phasing_Rep_SNP rows in the table because the group contains more than one single SNP of interest. Expanding the group allows for better comparison with the single SNP analysis.

  1. Cells with pink borders show haplotype analysis for paternal and maternal association study in the Framingham cohort, including coefficients and p-values. The results also include parental inheritance contrast coefficients and p-values for the representative SNPs. Pink-highlighted cells show the significant contrast p-values and the corresponding representative SNPs.

  2. Cells with orange borders show paternal and maternal association analysis and contrast results in the Framingham cohort for the 10 targeted single SNPs. Orange-highlighted cells indicate the parental inheritance contrast p-value of SNPs showing POE.

  3. Cells with green borders present results from the Sorbs cohort, with green-highlighted cells indicating the p-values of POE SNPs.

  4. Cells with violet borders display results from the German Trios cohort, with violet-highlighted cells showing the p-values of POE SNPs.

6. Conclusion

Intron_1: Haplotype analysis of Framingham identified four representative SNPs with parental origin effects (POE). Two SNPs (rs12447107 and rs28711250) exhibited stronger negative paternal effects, while rs12447481 showed a stronger negative maternal effect. SNP rs8047587 demonstrated stronger positive maternal effects. Notably, rs8047587, along with two POE SNPs from the Sorbs dataset (rs9939973 and rs1121980), belongs to a highly correlated haplotype group in linkage disequilibrium (LD). In the Sorbs dataset, the latter two SNPs displayed stronger positive paternal effects. In the Framingham cohort’s single SNP analysis, rs9939973 and rs1121980 showed stronger positive maternal effects, reflecting a consistent trend among SNPs from the same haplotype group.

Intron_2: Haplotype analysis of Framingham individuals revealed SNP rs75547181 with stronger negative paternal effects, while SNP rs10852522 from the German Trios cohort demonstrated stronger maternal effects.

Intron_3: A representative SNP(rs16952577) from the Framingham haplotype analysis indicated stronger positive maternal effects. Additionally, two SNPs (rs17818902 and rs17818920) from the same haplotype group consistently showed stronger positive maternal effects in both Framingham and German Trios cohorts.

The findings indicate that POE on offspring BMI varies by intron and specific SNPs. Some SNPs exhibit consistent maternal or paternal effects across different cohorts, while others display different parental effects. Therefore, it is difficult to conclude that the hypothesis is fully supported. This study highlights the complex genetic influences on BMI and the significance of considering both maternal and paternal genetic contributions in obesity-related research.