Exploring the genetic risk of vitamin B12 deficiency: A Phenome-wide association study of CLYBL in All of Us
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Vitamin B12, a critical micronutrient, plays an indispensable role in various biochemical processes within the human body, including DNA synthesis, red blood cell formation, and neurological function. Recent research has illuminated the significance of a specific gene, CLYBL, in modulating vitamin B12 levels. Located on chromosome 13, CLYBL encodes a mitochondrial citramalyl-CoA lyase that falls into a unique category of polymorphic human genes characterized by bi-allelic, loss of function (LoF) variants, which do not cause overtly recognized disease. Approximately 2.7% of human chromosomes exhibit a loss of CLYBL function due to a single nucleotide polymorphism (SNP rs41281112), which results in a premature stop codon at Arginine 259, leading to a truncated and non-functional protein. Homozygosity for this mutation correlates with a significant reduction in circulating vitamin B12 levels with an uncertain effect on long term health. The primary objective of this study was to explore associations between this CLYBL variant and various phenotypes within the All of Us cohort, utilizing a phenome-wide association study (PheWAS) approach.
Methods:
For this study, we employed phenome-wide association studies (PheWAS) focusing on the CLYBL gene variant (rs41281112) hypothesized to be pathogenic. We transformed the extensive electronic health record (EHR) data into phenotypic codes (phecodes) using the International Classification of Diseases (ICD) to phecodes mapping system. This approach allowed for a comprehensive, phenotype-based analysis of the genetic variant’s impact. We incorporated transancestry genomic data to ensure a broad representation of genetic backgrounds. Our cohort consisted of 245,386 individuals with whole genome sequencing data in All of Us, including 10,561 heterozygous and 178 homozygous individuals for CLYBL. We first applied an additive model for this cohort in our PheWAS to discern the association between the CLYBL variant and various health outcomes. Then we ran another PheWAS with homozygous and wild-type individuals only.
Results:
For the additive model, no phecodes passed the Bonferroni correction. However, the homozygous vs wild-type PheWAS included polycythemia (OR=2.97 [1.79-4.93]) and spinal cord injury without evidence of spinal bone injury (OR=4.44 [2.19-9.02]) that survived the Bonferroni correction. These positive associations suggest a broader impact of the CLYBL gene on human health than previously understood.
Conclusion:
The preliminary findings identified associations between this CLYBL variant, and a range of clinical conditions, some of which may be related to perturbed vitamin B12 metabolism. To further elucidate these relationships, ongoing studies are focused on in-depth analysis of laboratory data from the All of Us cohort, with a particular emphasis on clinical and laboratory manifestations associated with homozygosity for the CLYBL variant. Additionally, ancestry specific PheWAS studies are underway to explore potential genetic and environmental modifiers that may influence the expression and consequences of the CLYBL variant across different populations.
Vitamin B12, a critical micronutrient, plays an indispensable role in various biochemical processes within the human body, including DNA synthesis, red blood cell formation, and neurological function. Recent research has illuminated the significance of a specific gene, CLYBL, in modulating vitamin B12 levels. Located on chromosome 13, CLYBL encodes a mitochondrial citramalyl-CoA lyase that falls into a unique category of polymorphic human genes characterized by bi-allelic, loss of function (LoF) variants, which do not cause overtly recognized disease. Approximately 2.7% of human chromosomes exhibit a loss of CLYBL function due to a single nucleotide polymorphism (SNP rs41281112), which results in a premature stop codon at Arginine 259, leading to a truncated and non-functional protein. Homozygosity for this mutation correlates with a significant reduction in circulating vitamin B12 levels with an uncertain effect on long term health. The primary objective of this study was to explore associations between this CLYBL variant and various phenotypes within the All of Us cohort, utilizing a phenome-wide association study (PheWAS) approach.
Methods:
For this study, we employed phenome-wide association studies (PheWAS) focusing on the CLYBL gene variant (rs41281112) hypothesized to be pathogenic. We transformed the extensive electronic health record (EHR) data into phenotypic codes (phecodes) using the International Classification of Diseases (ICD) to phecodes mapping system. This approach allowed for a comprehensive, phenotype-based analysis of the genetic variant’s impact. We incorporated transancestry genomic data to ensure a broad representation of genetic backgrounds. Our cohort consisted of 245,386 individuals with whole genome sequencing data in All of Us, including 10,561 heterozygous and 178 homozygous individuals for CLYBL. We first applied an additive model for this cohort in our PheWAS to discern the association between the CLYBL variant and various health outcomes. Then we ran another PheWAS with homozygous and wild-type individuals only.
Results:
For the additive model, no phecodes passed the Bonferroni correction. However, the homozygous vs wild-type PheWAS included polycythemia (OR=2.97 [1.79-4.93]) and spinal cord injury without evidence of spinal bone injury (OR=4.44 [2.19-9.02]) that survived the Bonferroni correction. These positive associations suggest a broader impact of the CLYBL gene on human health than previously understood.
Conclusion:
The preliminary findings identified associations between this CLYBL variant, and a range of clinical conditions, some of which may be related to perturbed vitamin B12 metabolism. To further elucidate these relationships, ongoing studies are focused on in-depth analysis of laboratory data from the All of Us cohort, with a particular emphasis on clinical and laboratory manifestations associated with homozygosity for the CLYBL variant. Additionally, ancestry specific PheWAS studies are underway to explore potential genetic and environmental modifiers that may influence the expression and consequences of the CLYBL variant across different populations.