Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys

Background: The melanocortin-4-receptor gene (MC4R) is part of the melanocortinergic pathway that controls energy homeostasis. In a recent meta-analysis, the MC4R V103I (rs2229616) polymorphism was shown to be associated with body weight regulation. Although no functional differences between the isoleucine comprising receptor and the wild type receptor have been detected as yet, this meta-analysis of 14 case–control studies reported a mild negative association with obesity (odds ratio (OR) 0.69, p = 0.03). However, evidence in a large population based study in a homogeneous population and a significant estimate of the change in quantitative measures of obesity is still lacking.     

A tagging SNP in INSIG2 is associated with obesity-related phenotypes among Samoans

Background  

A genome wide association study found significant association of a sequence variant, rs7566605, in the insulin-induced gene 2 (INSIG2) with obesity. However, the association remained inconclusive in follow-up studies. We tested for association of four tagging SNPs (tagSNPs) including this variant with body mass index (BMI) and abdominal circumference (ABDCIR) in the Samoans of the Western Pacific, a population with high levels of obesity.     

INSIG2 gene rs7566605 polymorphism is associated with severe obesity in Japanese

The single nucleotide polymorphism (SNP) rs7566605 in the upstream region of the insulin-induced gene 2 (INSIG2) is associated with the obesity phenotype in many Caucasian populations. In Japanese, this association with the obesity phenotype is not clear. To investigate the relationship between rs7566605 and obesity in Japanese, we genotyped rs7566605 from severely obese subjects [n = 908, body mass index (BMI) >/= 30 kg/m(2)] and normal-weight control subjects (n = 1495, BMI < 25 kg/m(2)). A case-control association analysis revealed that rs7566605 was significantly associated with obesity in Japanese. The P value in the minor allele recessive mode was 0.00020, and the odds ratio (OR) adjusted for gender and age was 1.61 [95% confidential interval (CI) = 1.24-2.09]. Obesity-associated phenotypes, which included the level of BMI, plasma glucose, hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure, were not associated with the rs7566605 genotype. Thus, rs7566605 in the upstream region of the INSIG2 gene was found to be associated with obesity, i.e., severe obesity, in Japanese.     

Potential association of INSIG2 rs7566605 polymorphism with body weight in a Chinese subpopulation

Herbert et al reported association with obesity of a common DNA variant rs7566605 at 10 kb upstream of the INSIG2 gene. We analyzed rs7566605 polymorphism in 3125 Chinese in a cross-sectional study. We found no significant association of rs7566605 polymorphism with body mass index (BMI) and waist circumference among all participants (P=0.52). However, if geographic location is considered, the C/C genotype of rs7566605 was marginally associated with increased levels of BMI and risk of obesity among individuals living in Shanghai (P=0.06), indicating that the C/C genotype may contribute to obesity in certain subpopulation among Chinese under certain environmental settings.     

Linkage study of fibrinogen levels: the Strong Heart Family Study

Background

A common SNP upstream of the INSIG2 gene, rs7566605 (g.-10,1025G>C, Chr2:118,552,255, NT_022135.15), was reported to be associated with obesity (Body Mass Index, [BMI]) in a genome-wide association scan using the Framingham Heart Study but has not been reproduced in other cohorts. As BMI is a relatively insensitive measure of adiposity that is subject to many confounding variables, we sought to determine the relationship between the INSIG2 SNP and subcutaneous fat volumes measured by MRI in a young adult population.

Methods

We genotyped the INSIG2 SNP rs7566605 in college-aged population enrolled in a controlled resistance-training program, (the Functional Polymorphism Associated with Human Muscle Size and Strength, FAMuSS cohort, n = 752 volunteers 18–40 yrs). In this longitudinal study, we examined the effect of the INSIG2 polymorphism on subcutaneous fat and muscle volumes of the upper arm measured by magnetic resonance imaging (MRI) before and after 12 wks of resistance training. Gene/phenotype associations were tested using an analysis of covariance model with age and weight as covariates. Further, the % variation in each phenotype attributable to genotype was determined using hierarchical models and tested with a likelihood ratio test.

Results

Women with a copy of the C allele had higher levels of baseline subcutaneous fat (GG: n = 139; 243473 ± 5713 mm³ vs. GC/CC: n = 181; 268521 ± 5003 mm³; p = 0.0011); but men did not show any such association. Men homozygous for the G ancestral allele showed a loss of subcutaneous fat, while those with one or two copies of the C allele gained a greater percentage of subcutaneous fat with resistance training (GG: n = 103; 1.02% ± 1.74% vs. GC/CC: n = 93; 6.39% ± 1.82%; p = 0.035).

Conclusion

Our results show that the INSIG2 rs7566605 polymorphism underlies variation in subcutaneous adiposity in young adult women and suppresses the positive effects of resistance training on men. This supports and extends the original finding that there is an association between measures of obesity and INSIG2 rs7566605 and further implicates this polymorphism in fat regulation.     

The common genetic variant upstream of INSIG2 gene is not associated with obesity in Indian population

The high incidence of obesity has resulted in increased morbidity and mortality worldwide. Obesity, a common lifestyle disorder, is caused by multiple factors with heredity playing a strong causal role. Recently, a genetic variation upstream of insulin-induced gene 2 (INSIG2) (rs7566605) has been reported to be associated with obesity in four separate cohorts. Because the lifestyle and food preferences of a large proportion of Indian population differ from the rest of the world, we studied the impact of this polymorphism with body mass index (BMI). The study consisted of two cohorts--1577 healthy individuals from three major linguistic lineages in India and 610 coronary artery disease cases and controls. In the two cohorts studied, no significant association was observed between the polymorphism and BMI. However, frequency of homozygous variant genotype was higher in non-obese individuals as compared with obese individuals in both cohorts although the difference was marginally significant only in the case-control cohort under the assumption of a recessive model. Furthermore, regardless of age and sex, mean BMI did not vary with genotype under the assumptions of recessive model. Thus, in contrast to earlier reports, the variant upstream of INSIG2 is not a determinant of BMI in Indian population.     

An INSIG2 Polymorphism Affects Glucose Homeostasis in Sardinian Obese Children and Adolescents

Allelic variants of a single nucleotide polymorphism (SNP), rs7566605, located approximately 10 kb upstream of the INSIG2 gene have been found in association with body weight and with other clinical features related to obesity in some populations but not in others. Our objective was to test the association of this SNP in obese children and adolescents from the genetically isolated population of Sardinia. We tested the association of rs7566605 with body mass index (BMI) and with serum glucose and insulin concentrations and a surrogate measure of insulin resistance (HOMA‐IR) in a cohort of 747 Sardinian obese children and adolescents. A case control analysis was performed using 548 ethnically‐matched healthy controls. Allelic frequencies of the SNP were similar between patients and controls. Mean glucose and insulin concentration and mean HOMA‐IR values were significantly higher in patients carrying the CC genotype than in the CG and GG carriers. In the patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), allele C was significantly more frequent than in controls. Although INSIG2 polymorphisms do not consistently associate with BMI, the observation of an association with glucose concentration would support a role for this gene in the metabolic complications of obesity.     

Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene

The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity [odds ratio (OR) ranging from 0.25 to 0.76, 0.001 < P-value < 0.05] and with modulation of body mass index (BMI) in general populations, in eight out of nine studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L toward obesity (OR = 0.52, P = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, P = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment.     

Combined effects of MC4R and FTO common genetic variants on obesity in European general populations

Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20–24% of the populations), subjects with three or four risk alleles (7–10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (~1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P?=?0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P?=?0.02) and 21% (P?=?0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P?=?0.02) and 0.27 g/cm³ (P?=?0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P?=?0.003 and P?=?0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P?=?0.008 and P?=?0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.     

Association analyses of the INSIG2 polymorphism in the obesity and cholesterol levels of Korean populations

Background  

While INSIG2 has been reported to be associated with BMI in many populations, conflicting results have prevented consensus over its role. In analyses of mice and cell cultures the gene has been found to be involved in the regulation of cholesterol synthesis; however, no relationship has been found with cholesterol metabolism in human epidemiological research. Therefore, this study attempts to assess the effect of rs7566605 near INSIG2 on both obesity- and cholesterol-related traits in Koreans.     

Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan–Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20–34) compared with 34 years (95% CI: 30–40) for wild-type individuals (hazard ratio (HR)=1.64, 95% CI: 1.04–2.58, P=0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28–37) compared with 41 years (95% CI: 32–48, HR=1.44, 95% CI: 1.08–1.93, P=0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28–34) compared with 44 years of age (95% CI: 38–53) in wild-type individuals (HR=2.48, 95% CI: 1.47–4.17, P=0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.     

The INSIG2 rs7566605 genetic variant does not play a major role in obesity in a sample of 24,722 individuals from four cohorts

Background  

In a genome-wide association study performed in the Framingham Offspring Cohort, individuals homozygous for the rs7566605 C allele located upstream of insulin-induced gene 2 (INSIG2) were reported to incur an increased risk of obesity. This finding was later replicated in four out of five populations examined. The goal of the study reported here was to assess the role of the INSIG2 single nucleotide polymorphism (SNP) in susceptibility to obesity in the prospective longitudinal Atherosclerosis Risk in Communities (ARIC) study (n = 14,566) and in three other cohorts: the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3,888), the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 4,766), and extremely obese and lean individuals ascertained at the University of Ottawa (n = 1,502). The combined study sample is comprised of 24,722 white, African-American, and Mexican-American participants.     

Successful Treatment with Atomoxetine of an Adolescent Boy with Attention Deficit/Hyperactivity Disorder,Extreme Obesity,and Reduced Melanocortin 4 Receptor Function

ObjectiveRecent case reports suggest a link between reduced melanocortinergic tone and both obesity and attention deficit / hyperactivity disorder (ADHD). We present the case of a 13-year-old, male, obese MC4R mutation carrier with ADHD.Case ReportThe boy carries a heterozygous mutation in the melanocortin 4 receptor gene (MC4R; Met281Val), that leads to a reduced receptor function. Dominant mutations of this type represent major gene effects for obesity. He participated in a lifestyle intervention program for obesity and received treatment with the selective norepinephrine re-uptake inhibitor atomoxetine for 31 months. The boy markedly reduced his BMI from 47.2 to 29.6 kg/m².ConclusionAtomoxetine proved to efficiently reduce weight in a severely obese MC4R mutation carrier with ADHD. We briefly discuss possible mechanisms for our observation, including evidence for the functional connectivity between melanocortinergic, dopaminergic, and norepinephrinergic brain circuitries.Key Words: Pharmacogenetics, Brain-derived neurotrophic factor, Weight loss, Appetite control, Methylphenidate     

Association study of MC4R with complex obesity and replication of the rs17782313 association signal

Recently, genome-wide association studies have discovered several single nucleotide polymorphisms (SNPs) involved in the etiology of complex obesity. A variant downstream from the melanocortin-4 receptor gene (MC4R), a gene known to be involved in monogenic obesity, was reported to be highly associated with BMI. In the present study, we performed a replication study with the previously reported SNP rs17782313. We also included 3 tagSNPs (rs8087522, rs11872992, and rs1943226) for the MC4R gene region in our study to understand the role of this gene in complex obesity. We genotyped all 4 SNPs in a population of 1049 obese cases (mean BMI=38.2±6.2) and 312 healthy lean individuals (mean BMI 22.0±1.7). We could confirm that rs17782313 is highly associated with complex obesity in our population (odds ratio=1.42, 95% CI 1.14-1.77, P=0.002). Furthermore, we found this SNP to be associated with BMI (B=0.92, 95% CI 0.19-1.65, P=0.01) and body weight (B=2.44, 95% CI 0.28-4.60, P=0.03). In addition, we could also detect an association between rs11872992 and complex obesity (odds ratio=0.74, 95% CI 0.57-0.98, P=0.03). Through conditional analysis, we demonstrate that this effect is independent from the rs17782313 association signal. No associations with obesity could be found for rs8087522 and rs1943226. In conclusion, we could replicate the previously reported association between rs17782313 and complex obesity. Furthermore, our data do not support the hypothesis that a SNP in MC4R causes the rs17782313 association signal.     

Serum concentrations of adiponectin,leptin, resistin,ghrelin and insulin and their association with obesity indices in obese normo- and hypertensive patients – pilot study

Introduction

Hypertension often coexists with obesity. Adipokines, ghrelin and insulin play important roles in the pathogenesis of both diseases. The aim of this study was to compare adiponectin, leptin, resistin, insulin and ghrelin mean serum concentrations and insulin resistance (HOMA-IR) in normo- and hypertensive patients with obesity.

Material and methods

All included patients were divided on the following groups: non-diabetic hypertensive patients with class I obesity (group A, n = 21) and class II/III obesity (group B, n = 10), and normotensive obese (class I)patients (group C, n = 7). Correlations between obesity indices (body mass index [BMI], waist-to-hip ratio [WHR], waist circumference [WC]), HOMA-IR, and hormone and adipokine serum levels were also analyzed.

Results

Leptin level and HOMA-IR were significantly higher in group B compared to group C (9.74 ±3.88 ng/ml vs. 4.53 ±3.00 ng/ml; p < 0.02 and 3.30 ±1.59 vs. 1.65 ±0.41; p < 0.02, respectively). A negative correlation between WC and adiponectin level (R = –0.6275; p < 0.01) and a positive correlation between WC and insulin concentration (R = 0.5122; p< 0.05) as well as with HOMA-IR (R = 0.5228; p < 0.02) were found in group A. Negative correlations between BMI and ghrelin level (R = –0.7052; p < 0.05), WHR and adiponectin level (R = –0.6912; p < 0.05) and WHR and leptin level (R = –0.6728; p < 0.05) were observed in group B.

Conclusions

Insulin resistance and leptin may be important pathogenic factors in hypertensive patients with severe obesity. Indices of abdominal obesity (WC, WHR) correlate better than BMI with HOMA-IR, insulin, adiponectin and leptin serum levels in hypertensive obese patients.     

A missense variant,p.(Ile269Asn), in MC4R as a secondary finding in a child with BCL11A-related intellectual disability

We describe a three year old female who underwent clinical exome sequencing and was diagnosed with BCL11A-related intellectual disability/Dias-Logan syndrome due to a de novo, heterozygous variant in the BCL11A gene, NM_018014.3:c.148C > T; p.(Gln50*). A missense variant in MC4R, NM_005912.3:c.806T > A; p.(Ile269Asn), was also reported as a secondary finding. In her family, her father, paternal aunt, and paternal uncle were all reported to have height and weight measurements suggestive of Class 3 obesity with BMI>40 kg/m². The MC4R gene is not currently listed among those recommended for reporting of secondary findings by the American College of Medical Genetics and Genomics (ACMG). The identification of genetic risk factors for obesity is an emerging field without established guidelines for the care of patients who are found to have a predisposing genetic variant for obesity as a secondary finding. Management suggestions include interventions for weight-management, early screening for obesity-related co-morbidities, such as diabetes and dyslipidemia, and targeted therapies, such as MC4R agonists.     

A sequence variant on 17q21 is associated with age at onset and severity of asthma

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0–5 years OR=1.51, P=6.89·10⁻⁹) and adolescence (age: 14–17 years OR=1.71, P=5.47·10⁻⁹). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.     

FGF21 signalling pathway and metabolic traits – genetic association analysis

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol – LDL-C, HDL-cholesterol – HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.     

Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors

IntroductionThe CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. CYP450 genes contain several single nucleotide polymorphisms (SNPs) that confer different activity towards the enzyme. The aim of our study was to analyze gene frequencies of allelic variants and their association with ifosfamide blood levels and patient prognosis.Material and methods148 DNA samples from children were analyzed. Genotyping was performed by real-time PCR with TaqMan probes and ifosfamide levels were determined in dried blood drop by UPLCMS/MS.ResultsIfosfamide levels increased according to the genotype, and patients with the variant rs1799853 in CYP2C9 genotype CC had lower levels of ifosfamide (median = 1.8 μmol/l, Q₂₅ 0.9–Q₇₅ 4.6) compared with patients with genotype TT + CT (median = 2.8 μmol/l, Q₂₅ 1.9–Q₇₅ 5.1), p < 0.001. In the case of the rs2740574 variant in the CYP3A4 gene, patients with normal genotype (TT) presented median = 1.4 μmol/l, (Q₂₅ 0.7–Q₇₅ 2.7), while patients with the CC + TC genotype had higher levels of ifosfamide (median = 2.0 μmol/l, Q₂₅ 1.0–Q₇₅ 4.3), p = 0.024. In addition, patients with CC + CT genotype of this variant had a higher risk of non-response to treatment compared to patients with TT genotype (RR = 1.3, 95% CI: 1.07–1.59, p = 0.03).ConclusionsPolymorphisms in CYP2C9 and CYP3A4 genes are associated with high levels of ifosfamide. In addition, the polymorphism rs2740574 in CYP3A4 was associated with a worse therapeutic response.     

The dystrophin gene and cognitive function in the general population

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (P<1 × 10⁻⁴), rs147546024:A>G showed strong association (β=1.786, P-value=2.56 × 10⁻⁴) with block-design test in the ERF study, while another variant rs1800273:G>A showed suggestive association (β=−0.465, P-value=0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A>G is an intronic variant, whereas rs1800273:G>A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values=0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.