Exploring the genetic determinants of serum phosphate through large-scale GWAS Biobank approach: towards the elucidation of the genetic architecture of human serum phosphate

Erasmus MC

Lay summary

We plan to perform a large-scale study to find the genetic determinants of serum phosphate levels. We consider this an important research project because P has been related to increased adverse consequences in public health.

Research aims: we plan to perform a large-scale study to find the genetic determinants of P and increase the current explained variance. We aim to study the epidemiology of P within UKBB, to assess statistical evidence of gender-interaction between P genetic determinants, and to test if there is evidence of causality -through Mendelian Randomization- between P and two important clinical outcomes specifically described within Rotterdam Study, namely COPD and fracture risk.

Scientific rationale: phosphorus is one of the most common elements, being involved in several homeostatic and structural processes. Phosphorus exists in tissues as phosphate. Despite these key roles, clinical settings characterized by a marked increase in P levels - or in P accumulation -without frank hyperphosphatemia- such as chronic kidney disease (CKD), are related to high morbidity and mortality. A linear relation between P and adverse events has been reported. Additionally, an increasing epidemiological evidence has shown that even normal P levels are related with several adverse outcomes in the general population, such as in mortality risk (all-cause, CVD and COPD) and in morbidity (fracture risk, atherosclerosis and CKD progression). Simultaneously, a clear gender difference has become consistently evident, with stronger associations in men than women. From a cardiovascular perspective, high P is able to induce vascular calcification through trans-differentiation of vascular smooth muscle cells; from a pulmonary perspective, high P is related to severe emphysema that is rescued when P normalizes. High P induces a phenotype of premature ageing, leading to the concept of phosphotoxicity. Yet, the adverse effects with increasing -but normal- P are worrisome and raise the question if there is a threshold above which P is toxic.

Project duration: approximately 24 months.

Public health impact: the discovery of P genetic determinants within a large dataset enriched with low frequency and rare variants allows the elucidation of P genetic architecture and potential gender differences, as suggested by epidemiologic studies. If P homeostasis truly differs by gender, it has an important impact in public health measurements undertaken to decrease the risk associated with increasing P in the general population. The discovery of P determinants increases the power of future Mendelian Randomization studies testing for causality.

Current scope:

Research questions 1. What are the genetic determinants of serum phosphate levels (P)? 2. What is the epidemiology of P within UKBB ? 3. Is there statistical evidence of a gender-interaction between P genetic determinants? 4. Is there evidence of a causal relationship between P and COPD and fracture risk? Research aim We plan to conduct a large-scale meta-analysis within the UK Biobank dataset in order to be able to detect genetic determinants of P and increase the variance explained by two previous GWAS meta-analyses in European and Japanese populations. From epidemiological studies there seems to be important gender differences in P levels and outcomes; we aim therefore to test for gender-dimorphism in P genetic architecture. Additionally, the association of P with several outcomes varies according to fasting; therefore, we aim to stratify analyses according to fasting. Through Mendelian Randomization, we aim to conduct post-GWAS assessment of causal relationships of P and COPD and fracture risk, recently described within Rotterdam Study. The increased availability of low-frequency/rare variants in the UKBB offers an opportunity to discover variants in this frequency spectrum, predicted to display larger genetic effects and to contribute to substantial heritability

New scope:

Research questions 5. Are there age-related sex differences in P? 6. Is there an association between loop and thiazide diuretics use and P? Research aims: The normal range for phosphate is age-adjusted in infants, but much less is known about age-related changes in serum phosphate later in life. There is increasing evidence for age-related sex differences in serum phosphate. We aim to study age-related sex-specific changes in serum phosphate. Thiazide and loop diuretics are considered to be among the most common drugs that have been linked to hypophosphatemia. We aim to study the association between loop and thiazide diuretic use and P levels and risk of hypophosphatemia.