Fig. 2: Co-localization of variants in genomic locus 2.

Genomic locus 2 overlaps with a region in which SNPs are predicted to alter RBL2 expression in the human brain (eQTLs). a, The GWAS evidence for association with age at onset of walking [−log₁₀(P value), y axis] is plotted against the statistical evidence of being an eQTL for RBL2 in human adult cerebellum⁴² [−log₁₀(P value), x axis] for each SNP (points) within a 2-Mb window around the GWAS peak. Points are coloured by linkage disequilibrium (LD) correlation with the lead SNP (rs17800727) and these values were used to define two groups. b, The SNPs from a are shown in the 2-Mbp genomic region (x axis, GRCh37) with protein-coding genes (top), GWAS evidence for association with age at onset [−log₁₀(P value), middle] and statistical evidence for RBL2 expression in human cerebellum [−log₁₀(P value), y axis, bottom]. Point colour matches a. c, A zoomed-in view of the peak indicated by dashed vertical lines in b shows the GWAS evidence for association with age at onset of walking [−log₁₀(P value), y axis] by genomic position (x axis, GRCh37). Colour indicates the MAF of each SNP. The locations of protein-coding genes in the region are indicated at the top. An SNP (rs17800727) that results in a missense variant (p.Tyr210Cys) in RBL2 is marked. d, Swarm, violin and boxplots showing the distribution of RBL2 expression in the prefrontal cortex (transcripts per million (TPM), y axis). Each point represents the expression of RBL2 in 1 of 87 prenatal human cortices (BrainVar⁴⁴) split by genotype into 3 groups on the basis of zygosity for the Group 2 50% MAF SNPs. The P value represents the difference between the homozygous alternate (N = 28) and homozygous reference (N = 30) groups. The centre is the median expression value. The lower and upper bounds of the box correspond to the first and third quartiles (the 25th and 75th percentiles). The upper/lower whiskers extend from the upper/lower bound to the largest/smallest value no further than 1.5× the interquartile range. Data beyond the end of the whiskers are outlying points and are plotted individually. Bars at the bottom indicate pairs of haplotypes (derived from the data shown in c making up each genotype). e, Structure of the RBL2 protein predicted by AlphaFold⁹⁵ with the location of rs17800727, p.Tyr210Cys in red⁹⁶.