Phosphorus

Introduction

Phosphorus is an essential mineral that plays a fundamental role in numerous biological processes throughout the human body. As a key structural component of bones and teeth, it is integral to skeletal health. Beyond its structural contributions, phosphorus, primarily in the form of phosphate, is critical for energy production (as part of ATP), nucleic acid synthesis (DNA and RNA), and cell signaling pathways. The body maintains tight regulation of phosphorus levels, particularly in the blood serum, to ensure proper physiological function.

Biological Basis of Phosphorus Regulation

The regulation of phosphorus involves a complex interplay between the kidneys, intestines, and bone, orchestrated by various hormones such as parathyroid hormone and vitamin D. The kidneys play a central role in maintaining phosphate homeostasis by reabsorbing filtered phosphate from the urine back into the bloodstream. This reabsorption is largely mediated by sodium-phosphate co-transporters, such as NPT2, which is encoded by theSLC34A1 gene.^{[1], [21]} SLC34A1is highly expressed in the kidney, and its function is critical for preventing excessive renal phosphate wasting.^[2]Another important enzyme involved in phosphate metabolism is alkaline phosphatase (ALPL).^{[2], [3], [4]}This enzyme is known to dephosphorylate various substrates and is crucial for skeletal mineralization. Genetic variations, specifically single nucleotide polymorphisms (SNPs), in genes likeSLC34A1 and ALPLhave been identified to influence circulating phosphorus concentrations.^{[5], [6], [21]} For instance, SNPs in ALPLhave been associated with plasma pyridoxal 5’-phosphate (PLP) levels, highlightingALPL’s role in vitamin B6 metabolism, which is interconnected with phosphate pathways.^{[4], [7]}

Clinical Relevance

Measuring phosphorus levels in the blood is a vital diagnostic tool in clinical practice. Abnormal concentrations, either too low (hypophosphatemia) or too high (hyperphosphatemia), can signal significant health issues. Hypophosphatemia can arise from various causes, including mutations in genes such asSLC34A1, which can lead to conditions like hypophosphatemic nephrolithiasis (kidney stones) and osteoporosis due to impaired renal phosphate reabsorption.^[2] Additionally, mutations in the ALPLgene are the genetic basis for hypophosphatasia, a rare inherited disorder characterized by defective bone mineralization.^[3]Conversely, hyperphosphatemia is frequently observed in patients with chronic kidney disease, where the kidneys’ ability to excrete excess phosphate is compromised. Therefore, monitoring phosphorus levels is essential for the diagnosis, management, and prognosis of kidney disease, bone disorders, and various endocrine and metabolic imbalances.

Social Importance

The appropriate balance of phosphorus is critical for maintaining overall health, bone integrity, and metabolic function, directly impacting an individual’s quality of life. Chronic imbalances can lead to severe health complications, ranging from weakened bones and kidney stones to cardiovascular issues, thereby increasing healthcare burdens and affecting daily functioning. Understanding the genetic underpinnings that influence phosphorus levels provides opportunities for advancements in personalized medicine. Identifying individuals with genetic predispositions to phosphorus dysregulation, such as those with variants inSLC34A1 or ALPL, could enable earlier diagnosis, targeted preventive strategies, and more effective therapeutic interventions, ultimately improving patient outcomes and public health.

Methodological and Statistical Rigor

Studies aiming to identify genetic loci for complex traits often encounter challenges in replicating initial findings, particularly for variants with low allele frequencies or smaller effect sizes. For instance, some genetic variants identified in initial genome-wide association studies (GWAS) may not consistently replicate in subsequent independent cohorts, indicating potential false positives or context-specific effects.^[8] The comparison of effect sizes between discovery and replication cohorts is crucial, as discrepancies or non-replication of risk alleles can inflate reported effect sizes and lead to an overestimation of a variant’s true impact.^[8] This necessitates careful interpretation of novel associations and emphasizes the need for robust replication efforts across diverse datasets.^[4] Establishing appropriate statistical significance thresholds is paramount in large-scale genetic analyses to control for Type I errors, often requiring permutation tests or genomic control corrections.^[8] Furthermore, the quality of genotype imputation, which infers ungenotyped variants, can significantly influence the reliability of associations; markers with low imputation quality are often excluded or require careful validation to avoid spurious findings.^[9] Accounting for familial relationships within cohorts through methods like linear mixed models is also essential to prevent inflation of association statistics due to shared ancestry .

Population and Phenotypic Heterogeneity

Genetic associations identified in studies of specific populations, such as Japanese.^[8] European.^[9] or Han Chinese.^[10] cohorts, may not be directly generalizable to other ancestral groups due to differences in allele frequencies, linkage disequilibrium patterns, and genetic architectures. Population stratification, where systematic differences in allele frequencies between cases and controls arise from ancestry differences, can lead to spurious associations if not adequately addressed through statistical adjustments like principal components analysis . This highlights the importance of multi-ethnic studies to confirm findings and understand the global genetic landscape of complex traits.

The precise definition and consistent of complex traits present inherent challenges. Variations in how a phenotype is ascertained or quantified across different studies or populations can introduce heterogeneity, making it difficult to combine results or compare findings accurately.^[9] For any complex biological trait, the choice of method, timing, and potential environmental influences on the phenotype can impact the power to detect genetic associations and the interpretability of identified loci.

Complex Genetic Architectures and Environmental Interactions

Genetic associations for complex traits are often influenced by intricate interactions with environmental factors, such as maternal smoking or alcohol consumption, which can modulate the effect of specific genetic variants.^[4] Disentangling these gene-environment interactions is critical but challenging, as many environmental confounders may be unmeasured or difficult to quantify. Furthermore, even with robust genetic discoveries, a significant portion of the heritability for many complex traits remains unexplained, pointing to the involvement of rare variants, epistatic interactions, or other complex genetic mechanisms not fully captured by current GWAS designs.^[4] Identifying statistical associations between genetic variants and a trait is an important first step, but it often represents only a small part of the complete biological picture. The functional consequences of associated variants and the underlying biological mechanisms by which they influence the trait are frequently not immediately apparent from GWAS results alone.^[4] Bridging the gap from statistical association to biological mechanism requires further experimental validation and functional studies, which remain significant knowledge gaps after initial genetic discoveries.

Variants

Genetic variations play a crucial role in the regulation of phosphorus levels within the body, influencing processes like bone mineralization, kidney reabsorption, and hormonal signaling. Several genes, includingALPL, SLC34A1, and FGF23, contain variants that have been linked to differences in serum phosphorus measurements. For instance, variants near or withinALPL(Alkaline Phosphatase, Liver/Bone/Kidney type), such asrs1697421 , rs1106357 , rs12132412 , and rs2275372 , can affect the activity of this enzyme, which is essential for bone mineralization and hydrolyzing phosphate-containing molecules. AlteredALPLactivity can directly impact the availability and metabolism of inorganic phosphate, thereby influencing circulating phosphorus levels.^[11] Similarly, the SLC34A1 gene, with its variant rs35716097 , encodes a sodium-phosphate cotransporter that is critical for reabsorbing phosphate in the kidney tubules. Genetic changes inSLC34A1can modify the efficiency of renal phosphate handling, directly altering the amount of phosphorus retained in the blood versus excreted in urine.^[11] The FGF23 gene, through variants like rs12368351 (located in the FGF23-FGF6intergenic region), is central to phosphate homeostasis, as its protein product, Fibroblast Growth Factor 23, signals the kidneys to excrete phosphate and reduces vitamin D activation. Variations in this pathway can lead to significant shifts in serum phosphorus concentrations.^[11]Other genes, while not directly encoding phosphate transporters, contribute to phosphorus regulation through their roles in broader metabolic and signaling pathways. TheIP6K3gene (Inositol Polyphosphate Kinase 3), with variants such asrs73743323 and rs9469578 , is involved in the synthesis of inositol polyphosphates, signaling molecules that participate in various cellular functions, including metabolism and potentially mineral balance. Changes inIP6K3activity might indirectly modulate pathways that influence phosphorus handling or utilization.^[11] The PHEXgene (Phosphate Regulating Endopeptidase Homolog, X-linked), exemplified byrs178710 , encodes an enzyme that regulates FGF23 activity. Dysfunctional PHEX can lead to elevated FGF23levels, causing excessive renal phosphate wasting and a condition known as X-linked hypophosphatemia. Thus, variants inPHEXcan significantly impact the hormonal control of serum phosphorus.^[11]Furthermore, several other genetic loci contribute to the complex regulation of phosphorus. TheNBPF3 gene (Neuroblastoma Breakpoint Family Member 3), near the ALPL gene and encompassing variants like rs1697421 , rs1106357 , and rs12132412 , is a gene with less understood function but its genomic location suggests potential regulatory interplay with nearby genes critical for mineral metabolism. Variations in such regions could exert subtle effects on gene expression that collectively influence phosphorus levels.^[11] Similarly, the ENPP3 gene (Ectonucleotide Pyrophosphatase/Phosphodiesterase 3), with variant rs17060705 , encodes an enzyme that hydrolyzes nucleotides and pyrophosphate, directly affecting the availability of inorganic phosphate and the regulation of pyrophosphate, which is crucial for preventing ectopic calcification and promoting proper bone mineralization. Alterations inENPP3activity due to genetic variants can therefore impact phosphate dynamics and overall mineral balance.^[11] Finally, genes like AHI1-DT (AHI1 Divergent Transcript), associated with rs947583 , and LINC01482 (Long Intergenic Non-Coding RNA 1482), with rs35186465 , represent non-coding RNA elements that can influence gene regulation and cellular processes. While their direct roles in phosphorus metabolism are still being elucidated, non-coding RNAs can modulate the expression of protein-coding genes involved in transport, signaling, or enzymatic activities that indirectly impact phosphorus homeostasis.^[11] The FERRY3 gene (Ferric Reductase Like 3), with variant rs2970818 , might also contribute to mineral balance through broader cellular functions, such as redox regulation or iron metabolism, which can have interconnected effects on overall physiological processes, including those that influence phosphorus levels.^[11]These variants highlight the intricate genetic architecture underlying serum phosphorus regulation and its implications for human health.

Key Variants

RS ID	Gene	Related Traits
rs1697421 rs1106357 rs12132412	NBPF3 - ALPL	vitamin B6 phosphorus Alzheimer disease, polygenic risk score C-reactive protein cerebrospinal fluid composition attribute, phosphoethanolamine
rs35716097	SLC34A1	phosphorus glomerular filtration rate cathepsin L2 blood urea nitrogen amount inflammatory bowel disease
rs12368351	FGF23 - FGF6	phosphorus
rs73743323 rs9469578	IP6K3	phosphorus
rs178710	PHEX	phosphorus
rs947583	AHI1-DT	phosphorus
rs2275372	ALPL	phosphorus
rs17060705	ENPP3 - RPL15P9	phosphorus lipid
rs35186465	LINC01482	phosphorus
rs2970818	FERRY3	phosphorus alkaline phosphatase calcium blood phosphate

Defining Phosphorus Levels as a Biological Phenotype

“Phosphorus level” is identified as a distinct biological phenotype within the context of comprehensive phenome-wide association studies.^[12]This classification as a phenotype signifies its role as a measurable characteristic amenable to genetic investigation, crucial for understanding its variability across populations and its impact on health. Operationally, the determination of phosphorus level involves its quantification in biological samples, serving as a direct indicator of an individual’s phosphorus status, which is fundamental to numerous physiological processes.^[12] Its inclusion in large-scale genomic analyses underscores its conceptual framework as a quantitative trait with potential genetic determinants.

Terminology and Approaches in Genomic Research

The term “Phosphorus level” refers to the concentration of phosphorus, a vital mineral, typically assessed in bodily fluids for research purposes. In the realm of genomic studies, the precise quantification of such metabolite levels is critical for identifying genetic associations; for instance, other plasma metabolites like homocysteine, folate, vitamin B12, and pyridoxal 5’-phosphate are measured using specific laboratory assays and reported in standardized units such as mmol/l, ng/ml, pg/ml, or pmol/ml respectively.^[13] These quantitative measurements are often subjected to data transformations, such as log-transformation, before genome-wide association analyses to ensure statistical validity.^[13] This standardized approach to and data processing is essential for robust genetic discovery.

Scientific Significance in Phenome-Wide Studies

The inclusion of “Phosphorus level” as a phenotype in extensive phenome-wide association studies highlights its scientific significance as a trait for genetic investigation.^[12]Such studies aim to uncover genetic underpinnings of various biological measures and their interrelationships, contributing to a deeper understanding of complex traits and metabolic health. By analyzing its heritability and genetic associations, researchers can elucidate its role in broader physiological contexts and potential links to disease.^[12]This approach allows for the systematic exploration of how genetic variations influence phosphorus homeostasis and its implications for overall physiological function.

Molecular and Cellular Pathways of Phospholipid Metabolism

Phosphorus is an essential element integral to the structure and function of numerous biomolecules, with phospholipids being a prime example. Phosphatidylcholines (PCs) are a major class of glycerophospholipids, fundamental components of cellular membranes that inherently contain a phosphate group. Their biosynthesis involves complex metabolic pathways where various fatty acids are incorporated. Specifically, the conversion of eicosatrienoyl-CoA (C20:3) to arachidonyl-CoA (C20:4) is a critical step in the synthesis of certain polyunsaturated fatty acids that are subsequently integrated into these phospholipids.^[14] These fatty acyl-CoAs then serve as building blocks for specific phosphatidylcholine species, such as PC aa C36:3 and PC aa C36:4, which represent modified substrates and products of key enzymatic reactions within the cell.^[14]The presence and concentration of these phosphorus-containing lipids are therefore direct reflections of active cellular metabolic processes.

Genetic Regulation of Fatty Acid Desaturation and Phospholipid Composition

The efficiency of specific enzymatic reactions, crucial for phospholipid synthesis, is subject to genetic control. The delta-5 desaturase enzyme, encoded by the FADS1 gene, plays a pivotal role in introducing double bonds into fatty acids, converting C20:3 into C20:4.^[14] Genetic mechanisms, such as polymorphisms within the FADS1 gene itself or its associated regulatory elements, can significantly impact the catalytic activity or overall protein abundance of this enzyme. A reduction in FADS1activity, for instance, leads to altered availability of fatty acyl-CoAs, specifically increasing eicosatrienoyl-CoA (C20:3) and decreasing arachidonyl-CoA (C20:4) for subsequent glycerophospholipid synthesis.^[14]This genetic influence directly dictates the cellular landscape of phosphorus-containing phospholipids, affecting the balance between species like PC aa C36:3 and PC aa C36:4.

Systemic Consequences of Altered Phospholipid Profiles

Disruptions in the genetic and molecular pathways governing phospholipid synthesis can have systemic consequences, impacting homeostatic balance across various tissues and organs. Changes in the efficiency of the delta-5 desaturase reaction, driven by FADS1polymorphisms, lead to measurable shifts in serum glycerophospholipid concentrations.^[14] For instance, a reduced FADS1 efficiency results in increased concentrations of PC aa C36:3 and decreased concentrations of PC aa C36:4 in the serum, which can be observed as a strong association between these phospholipid levels and the FADS1 polymorphism.^[14]These alterations in the circulating lipid profile, particularly those involving phosphorus-containing molecules, can serve as indicators of underlying metabolic states or predispositions to certain physiological conditions, reflecting broader systemic consequences of genetic variations on fundamental cellular processes.

Phospholipids as Indicators of Metabolic Efficiency

The concentrations of specific glycerophospholipids in serum can serve as insightful indicators of metabolic efficiency and enzymatic activity. The ratio between product-substrate pairs of the delta-5 desaturase reaction, such as [PC aa C36:4]/[PC aa C36:3], provides a robust measure of the FADS1 enzyme’s effectiveness.^[14] Studies demonstrate that while glycerophospholipids with three double bonds show no significant association with FADS1 polymorphisms, their corresponding counterparts with four double bonds exhibit strong associations, reflecting the enzyme’s role in desaturation.^[14]Therefore, monitoring these phosphorus-containing lipid ratios offers a valuable non-invasive approach to assess the functional state of critical metabolic pathways, highlighting how phosphorus compounds are integral to cellular signaling and overall metabolic health.

Genetic Epidemiology of Serum Phosphorus Levels

Large-scale cohort studies and biobank initiatives have significantly advanced the understanding of genetic determinants influencing serum phosphorus levels in general populations. Genome-wide association studies (GWAS) have identified common genetic variants associated with circulating phosphorus concentrations, providing insights into the polygenic nature of phosphorus homeostasis.^[5]For instance, quantitative trait locus (QTL) analysis for serum phosphorus, conducted within a study involving 2,085 individuals, identified specific genetic markers likers11746443 as influencing phosphorus levels.^[2]These studies utilize extensive genomic data alongside biochemical measurements to uncover the genetic architecture underlying variability in phosphorus, highlighting the utility of large sample sizes and advanced statistical methods in epidemiological research.

Such population-level genetic investigations contribute to understanding the prevalence patterns of phosphorus dysregulation and identifying individuals potentially at higher risk for conditions related to abnormal phosphorus levels. The methodology typically involves genotyping thousands of participants and correlating single-nucleotide polymorphisms (SNPs) with observed phosphorus concentrations, adjusted for demographic factors. These findings have broad implications for public health, suggesting that genetic predisposition plays a role in maintaining phosphorus balance and could inform strategies for monitoring and intervention in diverse populations.

Cross-Population Genetic Studies and Ancestry-Specific Effects

Population studies have revealed variations in the genetic influences on phosphorus levels across different ethnic and geographic groups. A genome-wide association study conducted in a Japanese population, for example, specifically identified novel susceptible loci impacting serum phosphorus, alongside other traits.^[2] This research underscores that genetic population structure can significantly affect the identification and interpretation of association studies, necessitating diverse cohorts to ensure representativeness and generalizability of findings across global populations.

Comparing genetic findings across different ancestries, such as those from Asian versus European populations, helps to elucidate population-specific genetic effects and the broader spectrum of genetic diversity influencing phosphorus metabolism. Methodologically, these cross-population comparisons involve analyzing data from distinct ethnic groups, considering potential differences in allele frequencies and linkage disequilibrium patterns, to identify both common and unique genetic variants associated with phosphorus levels. This approach is crucial for understanding how genetic predispositions might vary epidemiologically across different demographic strata.

Monogenic Disorders and Their Impact on Phosphorus Homeostasis

Beyond common genetic variants, population studies also encompass the investigation of rare monogenic disorders that profoundly impact phosphorus homeostasis, illustrating the severe end of the spectrum of genetic influence. Hypophosphatasia, an inherited metabolic bone disease, serves as a prime example, resulting from different missense mutations at the tissue-nonspecific alkaline phosphatase gene (ALPL) locus.^[15]These mutations lead to impaired function of alkaline phosphatase, an enzyme critical for skeletal mineralization and vitamin B6 metabolism.^[6]Epidemiological observations in individuals with hypophosphatasia reveal markedly increased circulating pyridoxal-5’-phosphate levels, further demonstrating the enzyme’s role in vitamin B6 metabolism and, indirectly, its influence on phosphorus regulation.^[13]Such studies, while focusing on rare conditions, provide fundamental insights into the biological pathways governing phosphorus levels and highlight how specific genetic defects can manifest as severe clinical phenotypes within a population. Understanding these mechanisms contributes to diagnosing and potentially developing targeted treatments for such conditions, impacting incidence rates and improving outcomes for affected individuals.

Frequently Asked Questions About Phosphorus

These questions address the most important and specific aspects of phosphorus based on current genetic research.

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1. My family has a history of weak bones; will I get them too?

It’s possible, as genetic factors can play a significant role in bone health. For instance, mutations in theALPLgene are the genetic cause of hypophosphatasia, an inherited disorder that leads to defective bone mineralization. Knowing your family history can help you and your doctor be proactive in monitoring your bone health.

2. I get kidney stones often; could my genes be a reason?

Yes, absolutely. Some people are genetically predisposed to kidney stones. Mutations in a gene called SLC34A1, which helps your kidneys reabsorb phosphate, can lead to conditions like hypophosphatemic nephrolithiasis, characterized by kidney stones and low phosphate levels.

3. Could how my body uses energy be linked to my phosphorus levels?

Yes, phosphorus is fundamental for energy production in your body, primarily as a component of ATP (adenosine triphosphate). If your phosphorus levels are consistently too low or too high, it can disrupt these crucial energy pathways and affect your overall physiological function, potentially leading to symptoms like fatigue.

4. Does how my body handles vitamin B6 affect my bones?

Surprisingly, yes, there’s a connection. The ALPLgene, which is critical for bone mineralization, also plays a role in vitamin B6 metabolism. Specific genetic variations inALPLhave been linked to your blood levels of pyridoxal 5’-phosphate (PLP), a form of vitamin B6, highlighting this intricate metabolic interplay.

5. Why is my doctor so focused on my phosphorus since I have kidney disease?

Your kidneys are crucial for maintaining the right balance of phosphorus. If you have chronic kidney disease, your kidneys struggle to excrete excess phosphate, which can lead to dangerously high levels (hyperphosphatemia). Monitoring phosphorus is essential to manage your kidney disease and prevent complications.

6. Could a DNA test tell me if I’m likely to have bone issues?

A DNA test could offer insights into your predisposition for certain bone issues. Identifying specific genetic variants in genes likeALPL or SLC34A1can indicate an increased risk for conditions like hypophosphatasia or other bone disorders, allowing for earlier diagnosis and more targeted preventive strategies.

7. Why do some people seem to have naturally strong bones and no kidney issues?

Individual differences in phosphorus regulation are often rooted in genetics. Variations in genes likeSLC34A1 and ALPLinfluence how efficiently your body reabsorbs phosphate in the kidneys or mineralizes your bones. These genetic factors can contribute to why some individuals are naturally more resilient to these conditions.

8. If my child has weak bones, could it be something they inherited?

Yes, absolutely. Some forms of weak bones, particularly those related to defective mineralization, can be inherited. A prime example is hypophosphatasia, which is caused by mutations in the ALPL gene passed down through families, leading to significant skeletal problems in children.

9. Why might my doctor suggest a phosphorus test even if I feel fine?

Even if you feel well, your doctor might suggest a phosphorus test as part of a routine check or if there’s a family history of related conditions. Early detection of subtle imbalances can help identify genetic predispositions or nascent issues before they lead to noticeable symptoms, enabling proactive health management.

10. Can my family background affect my risk for phosphorus problems?

Yes, your family background and ethnicity can influence your genetic risk. Genetic associations with phosphorus levels or related conditions can differ between various populations, such as Japanese, European, or Han Chinese cohorts, meaning specific risks might be more prevalent or identified differently based on ancestry.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Oddsson, A. et al. “Common and rare variants associated with kidney stones and biochemical traits.” Nat Commun, vol. 6, 2015, p. 7607.

[2] Urabe, Y. et al. “A genome-wide association study of nephrolithiasis in the Japanese population identifies novel susceptible Loci at 5q35.3, 7p14.3, and 13q14.1.” PLoS Genet, vol. 8, no. 3, 2012, e1002566.

[3] Whyte, M. P. “Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization.”Endocr. Rev., vol. 15, 1994, pp. 439–461.

[4] Haaland, OA. “A genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption.”F1000Res, vol. 8, 2019, p. 1162.

[5] Kestenbaum, B. et al. “Common genetic variants associate with serum phosphorus concentration.”J. Am. Soc. Nephrol., vol. 21, 2010, pp. 1223–1232.

[6] Henthorn, P. S. et al. “Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.”Proc Natl Acad Sci USA, vol. 89, 1992, pp. 9924–9928.

[7] Carter, T. C. et al. “Common Variants at Putative Regulatory Sites of the Tissue Nonspecific Alkaline Phosphatase Gene Influence Circulating Pyridoxal 5’-Phosphate Concentration in Healthy Adults.”J Nutr, vol. 145, no. 7, 2015, pp. 1385-1392.

[8] Ishigaki, K. et al. “Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.” Nat Genet, vol. 52, no. 8, 2020, pp. 855–863.

[9] Stuart, PE. et al. “Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.”Am J Hum Genet, vol. 97, no. 6, 2015, pp. 816–833.

[10] He, J. et al. “Genome-wide association study identifies 8 novel loci associated with blood pressure responses to interventions in Han Chinese.” Circ Cardiovasc Genet, vol. 7, no. 1, 2014, pp. 69–77.

[11] Hwang, S. J., et al. “A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study.” BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, p. S10.

[12] Choe, Eun Kyoung, et al. “Leveraging deep phenotyping from health check-up cohort with 10,000 Korean individuals for phenome-wide association study of 136 traits.” Scientific Reports, vol. 12, no. 1, 2022, p. 2100.

[13] Hazra, A. et al. “Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway.” Hum Mol Genet, vol. 18, no. 23, 2009, pp. 4677–4687.

[14] Gieger, C., et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, vol. 5, no. 11, 2009, e1000694.

[15] Tanaka, T. et al. “Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations.”Am J Hum Genet, vol. 84, no. 4, 2009, pp. 477–482.