Sex-different interrelationships of rs945270, cerebral gray matter volumes, and attention deficit hyperactivity disorder: a region-wide study across brain

Abstract

Previous genome-wide association studies (GWAS) reported that the allele C of rs945270 of the kinectin 1 gene (KTN1) most significantly increased the gray matter volume (GMV) of the putamen and modestly regulated the risk for attention deficit hyperactivity disorder (ADHD). On the other hand, ADHD is known to be associated with a reduction in subcortical and cortical GMVs. Here, we examined the interrelationships of the GMVs, rs945270 alleles, and ADHD symptom scores in the same cohort of children. With data of rs945270 genotypes, GMVs of 118 brain regions, and ADHD symptom scores of 3372 boys and 3129 girls of the Adolescent Brain Cognition Development project, we employed linear regression analyses to examine the pairwise correlations adjusted for the third of the three traits and other relevant covariates, and examine their mediation effects. We found that the major allele C of rs945270 modestly increased risk for ADHD in males only when controlling for the confounding effects of the GMV of any one of the 118 cerebral regions (0.026 ≤ p ≤ 0.059: Top two: left and right putamen). This allele also significantly increased putamen GMV in males alone (left p = 2.8 × 10−5, and right p = 9.4 × 10−5; α = 2.1 × 10−4) and modestly increased other subcortical and cortical GMVs in both sexes (α < p < 0.05), whether or not adjusted for ADHD symptom scores. Both subcortical and cortical GMVs were significantly or suggestively reduced in ADHD when adjusted for rs945270 alleles, each more significantly in females (3.6 × 10−7 ≤ p < α; Top two: left pallidum and putamen) and males (3.5 × 10−6 ≤ p < α), respectively. Finally, the left and right putamen GMVs reduced 14.0% and 11.7% of the risk effects of allele C on ADHD, and allele C strengthened 4.5% (left) and 12.2% (right) of the protective effects of putamen GMVs on ADHD risk, respectively. We concluded that the rs945270-GMVs-ADHD relationships were sex-different. In males, the major allele C of rs945270 increased risk for ADHD, which was compromised by putamen GMVs; this allele also but only significantly increased putamen GMVs that then significantly protected against ADHD risk. In females, the top two GMVs significantly decreasing ADHD risk were left pallidum and putamen GMVs. Basal ganglia the left putamen in particular play the most critical role in the pathogenesis of ADHD.

Male-specific, replicable and functional roles of genetic variants and cerebral gray matter volumes in ADHD: a gene-wide association study across KTN1 and a region-wide functional validation across brain

“…The affected subcortical structures included primarily the BG—caudate, putamen, nucleus accumbens and pallidum. In the BG, the GMV of the putamen was most significantly and reliably affected by this set of KTN1 ADHD-risk alleles, consistent with the report that KTN1 was the most significant gene regulating the GMV of putamen [ 54 ], and the putamen GMV was the most significant regulator among all brain regions mediating the association between KTN1 and ADHD [ 83 ].…”

Genome‐wide DNA methylation analysis of aggressive behaviour: a longitudinal population‐based study

“…Colocalization analyses. We next examined whether methylation quantitative trait locus (mQTL) SNPs associated with our LHA-associated methylation sites colocalized with risk genes reported in GWAS studies performed on a number of LHA-related traits including general cognitive function (Davies et al, 2015) educational attainment (Adams, Tielbeek, Boutwell, & Broad Antisocial Behavior, 2022), risk-taking behaviour (Fernandez-Castillo, Cabana-Dominguez, Corominas, & Cormand, 2022, volume of the nucleus caudatus (Satizabal et al, 2019), volume of the putamen (Luo et al, 2022) and subjective well-being (Zhou et al, 2017). We obtained cis mQTLs associated with the top DMPs from the Genetics of DNA Methylation Consortium (goDMC) (Min et al, 2021).…”

Gray matter volumetric correlates of attention deficit and hyperactivity traits in emerging adolescents

“…We speculate that these volumetric correlates may more broadly represent neural markers of sex differences in clinical manifestations, including greater impulsivity in boys than in girls with ADHD 119 – 121 , which should be explored further. Studies investigating the heritability, particularly those involving the computation of polygenic risk scores, of both neural and behavioral markers would help addressing the inter-relationships between gene, brain, and behavior in ADHD 122 .…”