Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

Abstract Background Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10−8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74–0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.

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Genome-Wide Association between the 2q33.1 Locus and Intracranial Aneurysm Susceptibility: An Updated Meta-Analysis Including 18,019 Individuals

Journal of Clinical Medicine ◽

10.3390/jcm8050692 ◽

2019 ◽

Vol 8 (5) ◽

pp. 692

Author(s):

Eun Pyo Hong ◽

Bong Jun Kim ◽

Jin Pyeong Jeon

Keyword(s):

Intracranial Aneurysm ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

European Ancestry ◽

Eqtl Analysis ◽

Genome Wide Association Studies ◽

Human Tissues ◽

Genome Wide ◽

A Genome

Previous genome-wide association studies did not show a consistent association between the BOLL gene (rs700651, 2q33.1) and intracranial aneurysm (IA) susceptibility. We aimed to perform an updated meta-analysis for the potential IA-susceptibility locus in large-scale multi-ethnic populations. We conducted a systematic review of studies identified by an electronic search from January 1990 to March 2019. The overall estimates of the “G” allele of rs700651, indicating IA susceptibility, were calculated under the fixed- and random-effect models using the inverse-variance method. Subsequent in silico function and cis-expression quantitative trait loci (cis-eQTL) analyses were performed to evaluate biological functions and genotype-specific expressions in human tissues. We included 4513 IA patients and 13,506 controls from five studies with seven independent populations: three European-ancestry, three Japanese, and one Korean population. The overall result showed a genome-wide significance threshold between rs700651 and IA susceptibility after controlling for study heterogeneity (OR = 1.213, 95% CI: 1.135–1.296). Subsequent cis-eQTL analysis showed significant genome-wide expressions in three human tissues, i.e., testis (p = 8.04 × 10−15 for ANKRD44), tibial nerves (p = 3.18 × 10−10 for SF3B1), and thyroid glands (p = 4.61 × 10−9 for SF3B1). The rs700651 common variant of the 2q33.1 region may be involved in genetic mechanisms that increase the risk of IA and may play crucial roles in regulatory functions.

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Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

Human Molecular Genetics ◽

10.1093/hmg/ddy327 ◽

2018 ◽

Vol 28 (1) ◽

pp. 166-174 ◽

Cited By ~ 109

Author(s):

Sara L Pulit ◽

Charli Stoneman ◽

Andrew P Morris ◽

Andrew R Wood ◽

Craig A Glastonbury ◽

...

Keyword(s):

Body Fat ◽

Association Studies ◽

Meta Analysis ◽

Fat Distribution ◽

Body Fat Distribution ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Abstract More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

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Genomic Variations in Susceptibility to Intracranial Aneurysm in the Korean Population

Journal of Clinical Medicine ◽

10.3390/jcm8020275 ◽

2019 ◽

Vol 8 (2) ◽

pp. 275 ◽

Cited By ~ 8

Author(s):

Eun Hong ◽

Bong Kim ◽

Steve Cho ◽

Jin Yang ◽

Hyuk Choi ◽

...

Keyword(s):

Intracranial Aneurysm ◽

Association Studies ◽

Large Population ◽

Genome Wide Association ◽

Korean Population ◽

Genome Wide Association Studies ◽

Medicine Research ◽

Genome Wide ◽

A Genome ◽

Significant Difference

Genome-wide association studies found genetic variations with modulatory effects for intracranial aneurysm (IA) formations in European and Japanese populations. We aimed to identify the susceptibility of single nucleotide polymorphisms (SNPs) to IA in a Korean population consisting of 250 patients, and 294 controls using the Asian-specific Axiom Precision Medicine Research Array. Twenty-nine SNPs reached a genome-wide significance threshold (5 × 10−8). The rs371331393 SNP, with a stop-gain function of ARHGAP32 (11q24.3), showed the most significant association with the risk of IA (OR = 43.57, 95% CI: 21.84–86.95; p = 9.3 × 10−27). Eight out of 29 SNPs—GBA (rs75822236), TCF24 (rs112859779), OLFML2A (rs79134766), ARHGAP32 (rs371331393), CD163L1 (rs138525217), CUL4A (rs74115822), LOC102724084 (rs75861150), and LRRC3 (rs116969723)—demonstrated sufficient statistical power greater than or equal to 0.8. Two previously reported SNPs, rs700651 (BOLL, 2q33.1) and rs6841581 (EDNRA, 4q31.22), were validated in our GWAS (Genome-wide association study). In a subsequent analysis, three SNPs showed a significant difference in expressions: the rs6741819 (RNF144A, 2p25.1) was down-regulated in the adrenal gland tissue (p = 1.5 × 10−6), the rs1052270 (TMOD1. 9q22.33) was up-regulated in the testis tissue (p = 8.6 × 10−10), and rs6841581 (EDNRA, 4q31.22) was up-regulated in both the esophagus (p = 5.2 × 10−12) and skin tissues (1.2 × 10−6). Our GWAS showed novel candidate genes with Korean-specific variations in IA formations. Large population based studies are thus warranted.

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A genome-wide association study on meat consumption in a Japanese population: the Japan Multi-Institutional Collaborative Cohort study

Journal of Nutritional Science ◽

10.1017/jns.2021.49 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yasuyuki Nakamura ◽

Akira Narita ◽

Yoichi Sutoh ◽

Nahomi Imaeda ◽

Chiho Goto ◽

...

Keyword(s):

Japanese Population ◽

Genetic Factors ◽

Association Studies ◽

Linear Regression Analysis ◽

Meat Consumption ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Abstract Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1–10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population.

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Causal association of adipokines with osteoarthritis: a Mendelian randomization study

Rheumatology ◽

10.1093/rheumatology/keaa719 ◽

2020 ◽

Author(s):

Jiayao Fan ◽

Jiahao Zhu ◽

Lingling Sun ◽

Yasong Li ◽

Tianle Wang ◽

...

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Knee Oa ◽

Genome Wide ◽

A Genome ◽

Weighted Median

Abstract Objective This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. Methods Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. Results The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13–5.09] and weighted median (OR: 2.94, 95% CI: 1.23–6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01–1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18–10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03–1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. Conclusions An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

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A Genome-Wide Association Study Identifies the Association between the 12q24 Locus and Black Tea Consumption in Japanese Populations

Nutrients ◽

10.3390/nu12103182 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3182

Author(s):

Kyohei Furukawa ◽

Maki Igarashi ◽

Huijuan Jia ◽

Shun Nogawa ◽

Kaoru Kawafune ◽

...

Keyword(s):

Alcohol Drinking ◽

Genetic Variants ◽

Association Studies ◽

Black Tea ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Tea Consumption ◽

Genome Wide ◽

A Genome ◽

Drinking Frequency

Several genome-wide association studies (GWASs) have reported the association between genetic variants and the habitual consumption of foods and drinks; however, no association data are available regarding the consumption of black tea. The present study aimed to identify genetic variants associated with black tea consumption in 12,258 Japanese participants. Data on black tea consumption were collected by a self-administered questionnaire, and genotype data were obtained from a single nucleotide polymorphism array. In the discovery GWAS, two loci met suggestive significance (p < 1.0 × 10−6). Three genetic variants (rs2074356, rs144504271, and rs12231737) at 12q24 locus were also significantly associated with black tea consumption in the replication stage (p < 0.05) and during the meta-analysis (p < 5.0 × 10−8). The association of rs2074356 with black tea consumption was slightly attenuated by the additional adjustment for alcohol drinking frequency. In conclusion, genetic variants at the 12q24 locus were associated with black tea consumption in Japanese populations, and the association is at least partly mediated by alcohol drinking frequency.

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A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans

Frontiers in Genetics ◽

10.3389/fgene.2021.669215 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hye-Won Cho ◽

Hyun-Seok Jin ◽

Yong-Bin Eom

Keyword(s):

Genetic Variants ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Association Studies ◽

Fat Distribution ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

A Genome

Most previous genome-wide association studies (GWAS) have identified genetic variants associated with anthropometric traits. However, most of the evidence were reported in European populations. Anthropometric traits such as height and body fat distribution are significantly affected by gender and genetic factors. Here we performed GWAS involving 64,193 Koreans to identify the genetic factors associated with anthropometric phenotypes including height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip ratio. We found nine novel single-nucleotide polymorphisms (SNPs) and 59 independent genetic signals in genomic regions that were reported previously. Of the 19 SNPs reported previously, eight genetic variants at RP11-513I15.6 and one genetic variant at the RP11-977G19.10 region and six Asian-specific genetic variants were newly found. We compared our findings with those of previous studies in other populations. Five overlapping genetic regions (PAN2, ANKRD52, RNF41, HGMA1, and C6orf106) had been reported previously but none of the SNPs were independently identified in the current study. Seven of the nine newly found novel loci associated with height in women revealed a statistically significant skeletal expression of quantitative trait loci. Our study provides additional insight into the genetic effects of anthropometric phenotypes in East Asians.

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A Genome-Wide Association Study of spontaneous preterm birth in a European population

F1000Research ◽

10.12688/f1000research.2-255.v1 ◽

2013 ◽

Vol 2 ◽

pp. 255 ◽

Cited By ~ 3

Author(s):

Wilfred Wu ◽

Erin A S Clark ◽

Tracy A Manuck ◽

M Sean Esplin ◽

Michael W Varner ◽

...

Keyword(s):

Preterm Birth ◽

Genetic Variants ◽

Association Studies ◽

European Population ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Spontaneous Preterm Birth ◽

Genome Wide ◽

A Genome ◽

Increased Risk

Background: Preterm birth is defined as a birth prior to 37 completed weeks’ gestation. It affects more than 10% of all births worldwide, and is the leading cause of neonatal mortality in non-anomalous newborns. Even if the preterm newborn survives, there is an increased risk of lifelong morbidity. Despite the magnitude of this public health problem, the etiology of spontaneous preterm birth is not well understood. Previous studies suggest that genetics is an important contributing factor. We therefore employed a genome-wide association approach to explore possible fetal genetic variants that may be associated with spontaneous preterm birth.Methods: We obtained preterm birth phenotype and genotype data from the National Center for Biotechnology Information Genotypes and Phenotypes Database (study accession phs000103.v1.p1). This dataset contains participants collected by the Danish National Birth Cohort and includes 1000 preterm births and 1000 term births as controls. Whole genomes were genotyped on the Illumina Human660W-Quad_v1_A platform, which contains more than 500,000 markers. After data quality control, we performed genome-wide association studies for the 22 autosomal chromosomes.Results: No single nucleotide polymorphism reached genome-wide significance after Bonferroni correction for multiple testing.Conclusion: We found no evidence of genetic association with spontaneous preterm birth in this European population. Approaches that facilitate detection of both common and rare genetic variants, such as evaluation of high-risk pedigrees and genome sequencing, may be more successful in identifying genes associated with spontaneous preterm birth.

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Genome-wide association studies of impulsive personality traits (BIS-11 and UPPSP) and drug Experimentation in up to 22,861 adult research participants

10.1101/414854 ◽

2018 ◽

Cited By ~ 1

Author(s):

Sandra Sanchez-Roige ◽

Pierre Fontanillas ◽

Sarah L. Elson ◽

Michelle Agee ◽

Babak Alipanahi ◽

...

Keyword(s):

Personality Traits ◽

Genetic Variants ◽

Sensation Seeking ◽

Association Studies ◽

Risk Tolerance ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Research Participants ◽

Genome Wide

AbstractBackgroundImpulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse.MethodsIn collaboration with the genetics company 23andMe, Inc., we performed several genome-wide association studies (GWAS) on measures of impulsive personality traits (the short version of the UPPSP Impulsive Behavior Scale, and the Barratt Impulsiveness Scale [BIS-11]) and drug experimentation (the number of drug classes an individual has tried in their lifetime) in up to 22,861 male and female adult research participants of European ancestry.ResultsImpulsive personality traits and drug experimentation showed SNP-heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with the UPPSP Sensation Seeking subscale (P = 8.3 × 10-9, rs139528938) and showed a suggestive association with drug experimentation (P = 3.0 × 10-7, rs2163971; r2 = 0.68 with rs139528938); CADM2 has been previously associated with measures of risky behaviors and self-reported risk tolerance, cannabis initiation, alcohol consumption, as well as information speed processing, body mass index (BMI) variation and obesity. Furthermore, genetic variants in the CACNA1I locus were significantly associated with the UPPSP Negative Urgency subscale (P = 3.8 × 10-8, rs199694726). Multiple subscales from both UPPSP and BIS showed strong genetic correlations (>0.5) with drug experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPSP and BIS subscales were genetically correlated with attention-deficit/hyperactivity disorder (rg = 0.30-0.51, p < 8.69 x 10-3), supporting their validity as endophenotypes.ConclusionsOur findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.

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Meta-analysis of genome-wide association studies for body fat distribution in 694,649 individuals of European ancestry

10.1101/304030 ◽

2018 ◽

Cited By ~ 1

Author(s):

Sara L. Pulit ◽

Charli Stoneman ◽

Andrew P. Morris ◽

Andrew R. Wood ◽

Craig A. Glastonbury ◽

...

Keyword(s):

Body Fat ◽

Association Studies ◽

Meta Analysis ◽

Fat Distribution ◽

Body Fat Distribution ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

AbstractOne in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

Download Full-text