Browsing by Subject "Polygenic risk score"

Now showing 1 - 10 of 11
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    An interpretable Alzheimer's disease oligogenic risk score informed by neuroimaging biomarkers improves risk prediction and stratification
    (Frontiers Media, 2023-10-26) Suh, Erica H.; Lee, Garam; Jung, Sang-Hyuk; Wen, Zixuan; Bao, Jingxuan; Nho, Kwangsik; Huang, Heng; Davatzikos, Christos; Saykin, Andrew J.; Thompson, Paul M.; Shen, Li; Kim, Dokyoon; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Introduction: Stratification of Alzheimer's disease (AD) patients into risk subgroups using Polygenic Risk Scores (PRS) presents novel opportunities for the development of clinical trials and disease-modifying therapies. However, the heterogeneous nature of AD continues to pose significant challenges for the clinical broadscale use of PRS. PRS remains unfit in demonstrating sufficient accuracy in risk prediction, particularly for individuals with mild cognitive impairment (MCI), and in allowing feasible interpretation of specific genes or SNPs contributing to disease risk. We propose adORS, a novel oligogenic risk score for AD, to better predict risk of disease by using an optimized list of relevant genetic risk factors. Methods: Using whole genome sequencing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n = 1,545), we selected 20 genes that exhibited the strongest correlations with FDG-PET and AV45-PET, recognized neuroimaging biomarkers that detect functional brain changes in AD. This subset of genes was incorporated into adORS to assess, in comparison to PRS, the prediction accuracy of CN vs. AD classification and MCI conversion prediction, risk stratification of the ADNI cohort, and interpretability of the genetic information included in the scores. Results: adORS improved AUC scores over PRS in both CN vs. AD classification and MCI conversion prediction. The oligogenic model also refined risk-based stratification, even without the assistance of APOE, thus reflecting the true prevalence rate of the ADNI cohort compared to PRS. Interpretation analysis shows that genes included in adORS, such as ATF6, EFCAB11, ING5, SIK3, and CD46, have been observed in similar neurodegenerative disorders and/or are supported by AD-related literature. Discussion: Compared to conventional PRS, adORS may prove to be a more appropriate choice of differentiating patients into high or low genetic risk of AD in clinical studies or settings. Additionally, the ability to interpret specific genetic information allows the focus to be shifted from general relative risk based on a given population to the information that adORS can provide for a single individual, thus permitting the possibility of personalized treatments for AD.
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    Common genetic polymorphisms contribute to the association between chronic lymphocytic leukaemia and non-melanoma skin cancer
    (Oxford University Press, 2021-08-30) Besson, Caroline; Moore, Amy; Wu, Wenting; Vajdic, Claire M.; de Sanjose, Silvia; Camp, Nicola J.; Smedby, Karin E.; Shanafelt, Tait D.; Morton, Lindsay M.; Brewer, Jerry D.; Zablotska, Lydia; Engels, Eric A.; Cerhan, James R.; Slager, Susan L.; Han, Jiali; Berndt, Sonja I.; Medical and Molecular Genetics, School of Medicine
    Background: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases. Methods: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02-1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08-1.38, Ptrend = 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus. Conclusion: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.
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    Exploring the relationship between polygenic risk for cannabis use, peer cannabis use, and the longitudinal course of cannabis involvement
    (Wiley, 2019-04) Johnson, Emma C.; Tillman, Rebecca; Aliev, Fazil; Meyers, Jacquelyn L.; Salvatore, Jessica E.; Anokhin, Andrey P.; Dick, Danielle M.; Edenberg, Howard J.; Kramer, John; Kuperman, Samuel; McCutcheon, Vivia V.; Nurnberger, John I., Jr.; Porjesz, Bernice; Schuckit, Marc; Tischfield, Jay; Bucholz, Kathleen K.; Agrawal, Arpana; Biochemistry and Molecular Biology, School of Medicine
    Background and aims: Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories across ages 12–30, and perceived peer cannabis use at ages 12–17. Design: Mixed effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership, and perceived peer cannabis use. Setting: USA Participants: From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1,167 individuals aged 12–26 years at their baseline (i.e., first) interview. Measurements: Key measurements included lifetime cannabis use (yes/no), frequency of past 12-month cannabis use, maximum lifetime frequency of cannabis use, cannabis use disorder (using DSM-5 criteria), and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (N = 162,082) genome-wide association study (GWAS) of cannabis use. Three trajectories reflecting no/low (n=844), moderate (n=137) and high (n=186) use were identified. PRS were significantly associated with trajectory membership (p=0.002 – 0.006, maximum conditional R2 = 0.014, ORs = 1.40 – 1.49). Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users (OR = 1.35, 95% C.I. = [1.04, 1.75], p = 0.023). Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR: 1.50 – 4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (p < 0.01). Conclusions: Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults.
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    Genetic Risk for Alcohol Use Disorder in Relation to Individual Symptom Criteria: Do Polygenic Indices Provide Unique Information for Understanding Severity and Heterogeneity?
    (medRxiv, 2024-09-23) Kim, Yongguk; Lane, Sean P.; Miller, Alex P.; Wilhelmsen, Kirk C.; Gizer, Ian R.; Psychiatry, School of Medicine
    Alcohol Use Disorder (AUD) is a heterogenous category with many unique configurations of symptoms. Previous investigations of AUD heterogeneity using molecular genetics methods studied the association between genetic liability and individual AUD symptoms at the latent level or focusing on a small number of genetic variants. Notably, these studies did not investigate potential severity differences between symptoms in their genetic analyses. Therefore, the current study aimed to examine the genetic risk for individual AUD symptom criteria by using a polygenic risk score (PRS) approach to assess the relative severity of each AUD symptom and test for associates with AUD symptoms above and beyond a unidimensional AUD construct. An AUD PRS was created using summary statistics obtained from published genome-wide association studies (GWAS), and Multiple Indicators Multiple Causes (MIMIC) models were employed to examine the effect of the PRS on overall AUD severity as well as on individual symptoms after accounting for this overall effect. The phenotypic severity of AUD symptoms was highly correlated with the genetic severity of AUD symptoms (r = 0.78). Results of MIMIC models indicated that the AUD PRS significantly predicted the AUD factor. Regression paths testing the unique, direct effects of the PRS on individual AUD symptoms, independent of the latent AUD factor, were not significant. These results imply that PRSs derived from GWAS of AUD influence symptom expression through a single genetic factor that is highly correlated with the relative severity of individual symptoms when measured at the phenotypic level. Item-level GWAS of AUD symptoms are needed to further parse heterogeneous symptom expression and allow for more nuanced tests of these conclusions.
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    Genome wide association studies of the Self-Rating of Effects of Ethanol (SRE)
    (Wiley, 2020-03) Lai, Dongbing; Wetherill, Leah; Kapoor, Manav; Johnson, Emma C.; Schwandt, Melanie; Ramchandani, Vijay A.; Goldman, David; Joslyn, Geoff; Rao, Xi; Liu, Yunlong; Farris, Sean; Mayfield, R. Dayne; Dick, Danielle; Hesselbrock, Victor; Kramer, John; McCutcheon, Vivia V.; Nurnberger, John; Tischfield, Jay; Goate, Alison; Edenberg, Howard J.; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Schuckit, Marc; Medical and Molecular Genetics, School of Medicine
    The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
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    The Impact of Peer Substance Use and Polygenic Risk on Trajectories of Heavy Episodic Drinking Across Adolescence and Emerging Adulthood
    (Wiley, 2017-01) Li, James J.; Cho, Seung Bin; Salvatore, Jessica E.; Edenberg, Howard J.; Agrawal, Arpana; Chorlian, David B.; Porjesz, Bernice; Hesselbrock, Victor; COGA Investigators; Dick, Danielle M.; Biochemistry and Molecular Biology, School of Medicine
    BACKGROUND: Heavy episodic drinking is developmentally normative among adolescents and young adults, but is linked to adverse consequences in later life, such as drug and alcohol dependence. Genetic and peer influences are robust predictors of heavy episodic drinking in youth, but little is known about the interplay between polygenic risk and peer influences as they impact developmental patterns of heavy episodic drinking. METHODS: Data were from a multisite prospective study of alcohol use among adolescents and young adults with genome-wide association data (n = 412). Generalized linear mixed models were used to characterize the initial status and slopes of heavy episodic drinking between age 15 and 28. Polygenic risk scores (PRS) were derived from a separate genome-wide association study for alcohol dependence and examined for their interaction with substance use among the adolescents' closest friends in predicting the initial status and slopes of heavy episodic drinking. RESULTS: Close friend substance use was a robust predictor of adolescent heavy episodic drinking, even after controlling for parental knowledge and peer substance use in the school. PRS were predictive of the initial status and early patterns of heavy episodic drinking in males, but not in females. No interaction was detected between PRS and close friend substance use for heavy episodic drinking trajectories in either males or females. CONCLUSIONS: Although substance use among close friends and genetic influences play an important role in predicting heavy episodic drinking trajectories, particularly during the late adolescent to early adult years, we found no evidence of interaction between these influences after controlling for other social processes, such as parental knowledge and broader substance use among other peers outside of close friends. The use of longitudinal models and accounting for multiple social influences may be crucial for future studies focused on uncovering gene-environment interplay. Clinical implications are also discussed.
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    Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples
    (Cambridge University Press, 2021) Johnson, Emma C.; Sanchez-Roige, Sandra; Acion, Laura; Adams, Mark J.; Bucholz, Kathleen K.; Chan, Grace; Chao, Michael J.; Chorlian, David B.; Dick, Danielle M.; Edenberg, Howard J.; Foroud, Tatiana; Hayward, Caroline; Heron, Jon; Hesselbrock, Victor; Hickman, Matthew; Kendler, Kenneth S.; Kinreich, Sivan; Kramer, John; Kuo, Sally I-Chun; Kuperman, Samuel; Lai, Dongbing; McIntosh, Andrew M.; Meyers, Jacquelyn L.; Plawecki, Martin H.; Porjesz, Bernice; Porteous, David; Schuckit, Marc A.; Su, Jinni; Zang, Yong; Palmer, Abraham A.; Agrawal, Arpana; Clarke, Toni-Kim; Edwards, Alexis C.; Biochemistry and Molecular Biology, School of Medicine
    Background: Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds. Methods: We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes. Results: In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16). Conclusions: AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
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    Predictability of polygenic risk score for progression to dementia and its interaction with APOE ε4 in mild cognitive impairment
    (BMC, 2021-08-31) Pyun, Jung‑Min; Park, Young Ho; Lee, Keon‑Joo; Kim, SangYun; Saykin, Andrew J.; Nho, Kwangsik; Radiology and Imaging Sciences, School of Medicine
    Background: The combinatorial effect of multiple genetic factors calculated as a polygenic risk score (PRS) has been studied to predict disease progression to Alzheimer's disease (AD) from mild cognitive impairment (MCI). Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excluding single nucleotide polymorphisms within the region surrounding the APOE gene. These studies may have missed the APOE genotype-specific predictability of PRS for disease progression to AD. Methods: We analyzed 732 MCI from the Alzheimer's Disease Neuroimaging Initiative cohort, including those who progressed to AD within 5 years post-baseline (n = 270) and remained stable as MCI (n = 462). The predictability of PRS including and excluding the APOE region (PRS+APOE and PRS-APOE) on the conversion to AD and its interaction with the APOE ε4 carrier status were assessed using Cox regression analyses. Results: PRS+APOE (hazard ratio [HR] 1.468, 95% CI 1.335-1.615) and PRS-APOE (HR 1.293, 95% CI 1.157-1.445) were both associated with a significantly increased risk of MCI progression to dementia. The interaction between PRS+APOE and APOE ε4 carrier status was significant with a P-value of 0.0378. The association of PRSs with the progression risk was stronger in APOE ε4 non-carriers (PRS+APOE: HR 1.710, 95% CI 1.244-2.351; PRS-APOE: HR 1.429, 95% CI 1.182-1.728) than in APOE ε4 carriers (PRS+APOE: HR 1.167, 95% CI 1.005-1.355; PRS-APOE: HR 1.172, 95% CI 1.020-1.346). Conclusions: PRS could predict the conversion of MCI to dementia with a stronger association in APOE ε4 non-carriers than APOE ε4 carriers. This indicates PRS as a potential genetic predictor particularly for MCI with no APOE ε4 alleles.
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    Progress in Polygenic Composite Scores in Alzheimer’s and other Complex Diseases
    (Elsevier, 2019-05) Chasioti, Danai; Yan, Jingwen; Nho, Kwangsik; Saykin, Andrew J.; BioHealth Informatics, School of Informatics and Computing
    Advances in high-throughput genotyping and next-generation sequencing (NGS) coupled with larger sample sizes brings the realization of precision medicine closer than ever. Polygenic approaches incorporating the aggregate influence of multiple genetic variants can contribute to a better understanding of the genetic architecture of many complex diseases and facilitate patient stratification. This review addresses polygenic concepts, methodological developments, hypotheses, and key issues in study design. Polygenic risk scores (PRSs) have been applied to many complex diseases and here we focus on Alzheimer's disease (AD) as a primary exemplar. This review was designed to serve as a starting point for investigators wishing to use PRSs in their research and those interested in enhancing clinical study designs through enrichment strategies.
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    Sibling Comparisons Elucidate the Associations between Educational Attainment Polygenic Scores and Alcohol, Nicotine, and Cannabis
    (Wiley, 2020-02) Salvatore, Jessica E.; Barr, Peter B.; Stephenson, Mallory; Aliev, Fazil; I-Chun Kuo, Sally; Su, Jinni; Agrawal, Arpana; Almasy, Laura; Bierut, Laura; Bucholz, Kathleen; Chan, Grace; Edenberg, Howard J.; Johnson, Emma C.; McCutcheon, Vivia V.; Meyers, Jacquelyn L.; Schuckit, Marc; Tischfield, Jay; Wetherill, Leah; Dick, Danielle M.; Biochemistry and Molecular Biology, School of Medicine
    Background and aims: The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis). Design: Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families. Setting: Six sites in the United States. Participants: European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample. Measurements: Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment. Findings: In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R2 0.13-0.20%). Conclusions: Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education).