Genome-Wide Association Study Identifies Genetic Risk Factors for Spastic Cerebral Palsy

Abstract

BACKGROUND Although many clinical risk factors of spastic cerebral palsy (CP) have been identified, the genetic basis of spastic CP is largely unknown. Here, using whole-genome genetic information linked to a deidentified electronic health record (BioVU) with replication in the UK Biobank and FinnGen, we perform the first genome-wide association study (GWAS) for spastic CP. OBJECTIVE To define the genetic basis of spastic CP. METHODS Whole-genome data were obtained using the multi-ethnic genotyping array (MEGA) genotyping array capturing single-nucleotide polymorphisms (SNPs), minor allele frequency (MAF) > 0.01, and imputation quality score (r2) > 0.3, imputed based on the 1000 genomes phase 3 reference panel. Threshold for genome-wide significance was defined after Bonferroni correction for the total number of SNPs tested (P < 5.0 × 10–8). Replication analysis (defined as P < .05) was performed in the UK Biobank and FinnGen. RESULTS We identify 1 SNP (rs78686911) reaching genome-wide significance with spastic CP. Expression quantitative trait loci (eQTL) analysis suggests that rs78686911 decreases expression of GRIK4, a gene that encodes a high-affinity kainate glutamatergic receptor of largely unknown function. Replication analysis in the UK Biobank and FinnGen reveals additional SNPs in the GRIK4 loci associated with CP. CONCLUSION To our knowledge, we perform the first GWAS of spastic CP. Our study indicates that genetic variation contributes to CP risk.

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

“…17,18 GWAS was performed as previously described. 19,20 Whole-genome genotyping was performed using HumanOmniExpressExome BeadChip (Illumina), Human-OmniExpress, HumanExome BeadChip (Illumina), UK BiLEVE Axiom Array (Applied Biosystems), or UK Biobank Axiom Array (Applied Biosystems). The 1000 genome, 21 Haplotype Reference Consortium, and IMPUTE4 (IMPUTE) 16 were used as reference panels to guide imputation of rare and nongenotyped variants.…”

Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

“…The copyright holder for this preprint this version posted March 14, 2022. ; https://doi.org/10.1101/2022.03.12.22272299 doi: medRxiv preprint described. 34,43 Splicing quantitative trait loci (sQTL) was used to determine the potential impact of a SNP on alternative splicing. 44 In addition, we used Haploreg, 45 a functional genomics tool to explore the function of variants in non-coding regions of the genome.…”

“…10 GWAS was performed as previously described. 34,35 Whole-genome genotyping was performed using Illumina HumanOmniExpressExome BeadChip. 10 Imputation was performed using the 1000 genome reference panel, 36 Haplotype Reference Consortium, or the UK10K using IMPUTE4 software.…”

“…Expression quantitative trait loci (eQTL) analysis, which estimates the functional effect of a SNP/loci on neighboring gene expression, was performed as previously 9 described. 34,43 Splicing quantitative trait loci (sQTL) was used to determine the potential impact of a SNP on alternative splicing. 44 In addition, we used Haploreg, 45 a functional genomics tool to explore the function of variants in non-coding regions of the genome.…”

Exome-wide association study identified genetic variants contributing to the risk of cerebral palsy

“…Over the past decade, genomewide association studies (GWASs) have emerged as one of the major approaches to identifying underlying genetic variants associated with CP-related diseases or traits, such as epilepsy and autism [24][25][26] . However, until 2021, only one GWAS was performed, among 604 patients with spastic CP, and this study identi ed an association of rs78686911 with European-originated spastic CP 27 . In the gnomAD database, the allele frequencies of rs78687911 in European and East-Asian populations were 0.032 and 0, respectively.…”