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Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation.

ABSTRACT: Cognitive impairment is prevalent in blood or marrow transplantation (BMT) recipients, albeit with inter-individual variability. We conducted a genome-wide association study of objective cognitive function assessed longitudinally in 239 adult BMT recipients for discovery and replicated in an independent cohort of 540 BMT survivors. Weighted genome-wide polygenic risk scores (PRS) were constructed using linkage disequilibrium pruned significant SNPs. Forty-four genome-wide significant SNPs were identified using additive (n = 3); codominant (n = 20) and genotype models (n = 21). Each additional copy of a risk allele was associated with a 0.28-point (p = 1.07 × 10^-8) to a 1.82-point (p = 6.7 × 10^-12) increase in a global deficit score. We replicated two SNPs (rs11634183 and rs12486041) with links to neural integrity. Patients in the top PRS quintile were at increased risk of cognitive impairment in discovery (RR = 1.95, 95%CI: 1.28-2.96, p = 0.002) and replication cohorts (OR = 1.84, 95%CI, 1.02-3.32, p = 0.043). Associations were stronger among individuals with lowest clinical risk for cognitive impairment. These findings support potential utility of PRS-based risk classification in the development of targeted interventions aimed at improving cognitive outcomes in BMT survivors.

SUBMITTER: Sharafeldin N

PROVIDER: S-EPMC9233077 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation.

Sharafeldin Noha N Zhang Jianqing J Singh Purnima P Bosworth Alysia A Chen Yanjun Y Patel Sunita K SK Wang Xuexia X Francisco Liton L Forman Stephen J SJ Wong F Lennie FL Ojesina Akinyemi I AI Bhatia Smita S

Bone marrow transplantation 20220404 6

Cognitive impairment is prevalent in blood or marrow transplantation (BMT) recipients, albeit with inter-individual variability. We conducted a genome-wide association study of objective cognitive function assessed longitudinally in 239 adult BMT recipients for discovery and replicated in an independent cohort of 540 BMT survivors. Weighted genome-wide polygenic risk scores (PRS) were constructed using linkage disequilibrium pruned significant SNPs. Forty-four genome-wide significant SNPs were i ...[more]

PMID: 35379913

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Project description:The genetic protective factors for cognitive decline in aging remain unknown. Predicting an individual's rate of cognitive decline-or with better cognitive resilience-using genetics will allow personalized intervention for cognitive enhancement and the optimal selection of target samples in clinical trials. Here, using genome-wide polygenic scores (GPS) of cognitive capacity as the genomic indicators for variations of human intelligence, we analyzed the 18-year records of cognitive and behavioral data of 8511 European-ancestry adults from the Wisconsin Longitudinal Study (WLS), specifically focusing on the cognitive assessments that were repeatedly administered to the participants with their average ages of 64.5 and 71.5. We identified a significant interaction effect between age and cognitive capacity GPS, which indicated that a higher cognitive capacity GPS significantly correlated with a slower cognitive decline in the domain of immediate memory recall (β = 1.86 × 10-1, p-value = 1.79 × 10-3). The additional phenome-wide analyses identified several associations between cognitive capacity GPSs and cognitive/behavioral phenotypes, such as similarities task (β = 1.36, 95% CI = (1.22, 1.51), p-value = 3.59 × 10-74), number series task (β = 0.94, 95% CI = (0.85, 1.04), p-value = 2.55 × 10-78), IQ scores (β = 1.42, 95% CI = (1.32, 1.51), p-value = 7.74 × 10-179), high school classrank (β = 1.86, 95% CI = (1.69, 2.02), p-value = 3.07 × 10-101), Openness from the BIG 5 personality factor (p-value = 2.19 × 10-14, β = 0.57, 95% CI = (0.42, 0.71)), and leisure activity of reading books (β = 0.50, 95% CI = (0.40, 0.60), p-value = 2.03 × 10-21), attending cultural events, such as concerts, plays, or museums (β = 0.60, 95% CI = (0.49, 0.72), p-value = 2.06 × 10-23), and watching TV (β = -0.48, 95% CI = (-0.59, -0.37), p-value = 4.16 × 10-18). As the first phenome-wide analysis of cognitive and behavioral phenotypes, this study presents the novel genetic protective effects of cognitive ability on the decline of memory recall in an aging population.

Project description:PurposeUsing a candidate gene approach, we tested the hypothesis that individual single nucleotide polymorphisms (SNPs) and gene-level variants are associated with cognitive impairment in patients with hematologic malignancies treated with blood or marrow transplantation (BMT) and that inclusion of these SNPs improves risk prediction beyond that offered by clinical and demographic characteristics.Patients and methodsIn the discovery cohort, BMT recipients underwent a standardized battery of neuropsychological tests pre-BMT and at 6 months, 1 year, 2 years, and 3 years post-BMT. Associations between 68 candidate genes and cognitive impairment were assessed using generalized estimating equation models. Elastic-Net regression was used to build Base (sociodemographic), Clinical, and Combined (Base plus Clinical plus genetic) risk prediction models of post-BMT impairment. An independent nonoverlapping cohort from the BMT Survivor Study with self-report of learning/memory problems (as identified by their health care provider) was used for model replication.ResultsThe discovery cohort included 277 participants (58.5% males; 68.6% non-Hispanic whites; and 46.6% allogeneic BMT recipients). Adjusting for BMT type, age at BMT, sex, race/ethnicity, and cognitive reserve, SNPs in the blood-brain barrier, telomere homeostasis, and DNA repair genes were significantly associated with cognitive impairment. Compared with the Clinical Model, the Combined Model had higher predictive power in both the discovery cohort (mean area under the receiver operating characteristic curve [AUC], 0.89; 95% CI, 0.85 to 0.93 v 0.77; 95% CI, 0.71 to 0.83; P = 1.24 × 10-9) and the replication cohort (AUC, 0.71; 95% CI, 0.66 to 0.76 v 0.63; 95% CI, 0.57 to 0.68; P = .004).ConclusionInclusion of candidate genetic variants enhanced the prediction of risk of post-BMT cognitive impairment beyond that offered by demographic/clinical characteristics and represents a step toward a personalized approach to managing patients at high risk for cognitive impairment after BMT.

Project description:BackgroundCognitive impairment in survivors of blood or bone marrow transplantation (BMT) is well documented. However, to the authors' knowledge, the clinical relevance of self-endorsed cognitive problems and their relation to objectively assessed cognitive impairment is not known.MethodsThe authors assessed cognitive impairment in 378 BMT recipients (median age, 52.2 years, 40% of whom were female and 68% of whom were non-Hispanic white) and 98 healthy controls at 5 predetermined time points: at baseline (before BMT) and at 6 months, 1 year, 2 years, and 3 years after BMT. Self-endorsed cognitive problems were evaluated using the Neuropsychological Impairment Scale (NIS) and correlated with a standardized 2-hour battery of objective cognitive testing at each time point. The authors examined the magnitude of difference in self-endorsed cognitive problems between BMT recipients and healthy controls, and the rate of change in scores over time. Multivariable analyses were used to identify clinical and/or demographic variables associated with self-endorsed cognitive problems. The authors also examined the association between cognitive impairment and returning to work after BMT.ResultsCompared with healthy controls, BMT recipients endorsed more cognitive problems (P < .001) at all time points, and the rate of change in NIS scores was found to be significantly greater in BMT recipients. Fatigue was associated with greater endorsement of cognitive problems at 1 year after BMT (odds ratio, 4.23; 95% CI, 2.1-8.3 [P < .001]). Overall, there was a statistically significant, modest correlation noted between self-endorsed cognitive problems and objective cognitive impairment (range, 0.401-0.445 [P ≤ .01]). Higher self-endorsed cognitive problems were associated with a 3.7-fold (P = .02) higher odds of not returning to work at 3 years after BMT.ConclusionsThe results of the current study demonstrated that self-endorsed cognitive problems can help to identify vulnerable patient subpopulations for detailed cognitive assessment and possible cognitive remediation.

Project description:BACKGROUND:Inherited susceptibility to common, complex diseases may be caused by rare, pathogenic variants ("monogenic") or by the cumulative effect of numerous common variants ("polygenic"). Comprehensive genome interpretation should enable assessment for both monogenic and polygenic components of inherited risk. The traditional approach requires two distinct genetic testing technologies-high coverage sequencing of known genes to detect monogenic variants and a genome-wide genotyping array followed by imputation to calculate genome-wide polygenic scores (GPSs). We assessed the feasibility and accuracy of using low coverage whole genome sequencing (lcWGS) as an alternative to genotyping arrays to calculate GPSs. METHODS:First, we performed downsampling and imputation of WGS data from ten individuals to assess concordance with known genotypes. Second, we assessed the correlation between GPSs for 3 common diseases-coronary artery disease (CAD), breast cancer (BC), and atrial fibrillation (AF)-calculated using lcWGS and genotyping array in 184 samples. Third, we assessed concordance of lcWGS-based genotype calls and GPS calculation in 120 individuals with known genotypes, selected to reflect diverse ancestral backgrounds. Fourth, we assessed the relationship between GPSs calculated using lcWGS and disease phenotypes in a cohort of 11,502 individuals of European ancestry. RESULTS:We found imputation accuracy r2 values of greater than 0.90 for all ten samples-including those of African and Ashkenazi Jewish ancestry-with lcWGS data at 0.5×. GPSs calculated using lcWGS and genotyping array followed by imputation in 184 individuals were highly correlated for each of the 3 common diseases (r2 = 0.93-0.97) with similar score distributions. Using lcWGS data from 120 individuals of diverse ancestral backgrounds, we found similar results with respect to imputation accuracy and GPS correlations. Finally, we calculated GPSs for CAD, BC, and AF using lcWGS in 11,502 individuals of European ancestry, confirming odds ratios per standard deviation increment ranging 1.28 to 1.59, consistent with previous studies. CONCLUSIONS:lcWGS is an alternative technology to genotyping arrays for common genetic variant assessment and GPS calculation. lcWGS provides comparable imputation accuracy while also overcoming the ascertainment bias inherent to variant selection in genotyping array design.

Dataset Information

Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation.

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Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation.

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