D2 dopamine receptor gene (DRD2) Taq1A (rs1800497) affects bone density

Abstract

Schizophrenia patients are susceptible to lower bone mineral density (BMD). However, studies exploring the genetic effects are lacking. Genes that affect the activity of antipsychotics may be associated with BMD, particularly in patients receiving long-term antipsychotic treatment. We aimed to explore the relationship between the dopamine receptor D 2 (DRD2) gene Taq1A (rs1800497) polymorphism and BMD in chronic schizophrenia patients. We recruited schizophrenia patients (n = 47) and healthy controls (n = 39) from a medical center in Taiwan and collected data that may affect BMD. Patients' BMD was measured by dual-energy X-ray absorptiometer (DEXA). DRD2 rs1800497 was genotyped through polymerase chain reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Among all participants, subjects with DRD2 rs1800497(T;T) allele had lower DEXA T score and DEXA Z score compared to those with rs1800497(C;T) and rs1800497(C;C) alleles (p = 0.008, 0.003, respectively). In schizophrenia patients, subjects with rs1800497(T;T) allele also had lower DEXA Z score compared to the other two alleles (p = 0.045). Our findings suggest that individuals with the DRD2 rs1800497(T;T) had lower BMD than those with the rs1800497(C;T) and rs1800497(C;C) genotypes. Therefore, genes should be considered as one of the risk factors of lower BMD. With an increasingly ageing society, decreased bone mineral density (BMD) is an issue worthy of more attention. The operational description of osteoporosis is a BMD value at the femoral neck of 2.5 standard deviations (SDs) or more below the young female adult mean (T-score less than or equal to − 2.5 SDs) 1. The World Health Organization (WHO) describes it as a "progressive systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture" 2. People suffering from osteoporosis are at an increased risk for bone fracture, thus also leading to disability, diminished quality of life, and mortality. Europe has for the greatest number of osteoporotic fractures (34.8%), which lead to the loss of more Disability Adjusted Life Years (DALYs) than common cancers, with the exception of lung cancer 3. In Asia, the average treatment cost of osteoporosis-related hip fracture is around US $2,943, which is roughly 18.95% of the countries' 2014 GDP/capita 4. Schizophrenia is among the most critical psychiatric diseases in the world. These patients have markedly premature mortality and a variety of physical comorbidities. Schizophrenia patients are at a greater risk for diabetes, chronic obstructive pulmonary disease (COPD), and influenza or pneumonia 5. Recent studies have indicated that schizophrenia is associated with reduced BMD and higher fracture risk 6,7. Hyperprolactinemia (HPRL) is a common side effect of schizophrenia patients taking such antipsychotics as first-generation antipsychotics (FGA) and certain second-generation antipsychotics (SGA). Some studies suggest a relationship between ...

The neglected association between schizophrenia and bone fragility: a systematic review and meta-analyses

“…Study characteristics: There were 17 studies published between 1997 and 2021 that examined associations between schizophrenia and BMD [49,50,[60][61][62][63][64][65][66][67][68][69][70][71][72][73][74]. The sample sizes ranged between 14 [70] to 229 [67] adults with schizophrenia.…”

“…Only one study was conducted within a population-based setting (Manitoba Bone Density Program database) [61], with all other studies conducted within clinical settings. Among these studies, 15 [49,50,60,[62][63][64][65][66][67][68][70][71][72][73][74] compared BMD between people with schizophrenia and a control group, one study [69] used reference data for age-and race-matched healthy males, while another study [61] compared the percentage of schizophrenia among people with low BMD and normal BMD. Seven studies [60,61,64,69,71,73] used an age-and sex-matched control group and other studies used only an age-matched [72] or sex-matched [49,65] control group.…”

“…Seven studies [60,61,64,69,71,73] used an age-and sex-matched control group and other studies used only an age-matched [72] or sex-matched [49,65] control group. The remaining studies used an aged-and sex-similar [70,74] or unmatched control group [50,62,63,66,67]. Two prospective studies [72,73] measured BMD before and after treatment with antipsychotic medication, of which we only included the baseline data (pre-treatment).…”

“…The highest number of sites assessed was reported by Liang et al [71], measuring multiple sites, including lumbar spine: L1, L2, L3, L4, and L1-4, hip: femoral neck, trochanter, Ward's triangle, total hip, and radius: one-third distal, ultra-distal, middle distal, and total radius ulna [71]. Thirteen studies [49, 50, 60, 62, 64-69, 71, 73, 74] reported BMD in g/cm 2 , while ten studies [49, 60-63, 66, 67, 69, 70, 72] reported T-scores and Z-scores were reported by five studies [50,62,64,69,72]. Findings: Among the 16 studies using a control group (including one study [69] using reference data as a comparator), 12 (75.0%) found significantly lower BMD in the schizophrenia group compared with a control group in at least one region or at least one patient subgroup [49,50,63,[65][66][67][68][69][70][71][72]74].…”

Dopamine, Immunity, and Disease

“…Treating rats with methylphenidate, which blocks dopamine reuptake and increases extracellular dopamine levels, led to a methylphenidate- and sex-dependent decrease in bone integrity due to increased osteoclast activity ( Uddin et al, 2018 ). Studies show that that polymorphisms in D2 and D4 are associated with reduced bone mineral density ( Yamada et al, 2003 ; Chiang et al, 2020 ). These data indicate that hyperprolactinemia-induced hypogonadism is not the sole mechanism by which dysregulation of dopaminergic signaling could regulate bone health and that other mechanisms may play a significant role in the pathogenesis of dopamine-mediated bone loss.…”