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

Abstract

Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene (KTN1) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10–5 ≤ p ≤ 0.039). The ADHD-risk alleles significantly increased basal ganglia (2.8 × 10–22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 < p ≤ 0.013). The ADHD-risk alleles also significantly reduced some cortical (right superior temporal pole, right rectus) and cerebellar but increased other cortical (0.007 ≤ p ≤ 0.050) GMVs. To conclude, we identified a set of replicable and functional risk KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

Predicting new onset thought disorder in early adolescence with optimized deep learning implicates environmental-putamen interactions

“…The putamen is a dopamine-enriched structure involved in motor control and learning where volumetric differences have previously been associated with schizophrenia spectrum disorders and degenerative neuropsychiatric conditions. (95) For example, volumetric decreases in the left putamen and caudate are specifically associated with the presence of delusions in first episode schizophrenia (FEP). (96) The left putamen is also well-associated with cognitive (rather than motor) aspects of language processing, in particular phonological processing, articulation and language discrimination, including suggestive links to dopamine metabolism.…”

Quantitative evaluation of brain volumes in drug-free major depressive disorder using MRI-Cloud method

“…At present there are also studies showing either unaltered [58] (e.g. MDD) or increased volumes in special neuropsychiatric conditions characterized by dopaminergic activation, such as schizophrenia and autism and OCD [12].…”

“…There are also interesting neuropsychiatry studies revealing increased putaminal volumes in attention-deficit hyperactivity disorder (ADHD), pain, smoking, obsessive-compulsive disorder (OCD), neuroleptic exposure, autism, bipolar depression, and schizophrenia [12]. However, it is still unclear if comorbid conditions other than anxiety might affect the specific volumes in MDD, especially when it comes to unexpected volume alterations, such as increased putaminal and amygdala volumes.…”

Parkinson's disease and Parkinsonism syndromes: Evaluating iron deposition in the putamen using magnetic susceptibility MRI techniques - A systematic review and literature analysis

“…The structure and volume of the PUT can be altered in various neurological and neuropsychiatric conditions [ 47 , 48 ], including PD [ 48 ], AD [ 49 , 50 ], amyotrophic lateral sclerosis (ALS) [ 51 , 52 ], obstructive sleep apnea (OSA) [ 53 , 54 ], and major depressive disorder (MDD) [ 55 ]. Parkinsonian Syndromes are notably associated with elevated iron concentration in the deep gray matter (DGM) nuclei [ [56] , [57] , [58] , [59] ].…”

“…Parkinsonian Syndromes are notably associated with elevated iron concentration in the deep gray matter (DGM) nuclei [ [56] , [57] , [58] , [59] ]. It has been suggested that the PUT is one of the primary regions affected by Parkinson's syndrome [ [60] , [61] , [62] , [63] ], which is age-dependent [ 48 , 59 , 64 ] and most prominently susceptible to the accumulation of iron [ 59 , 64 ]. Several studies, including meta-analyses, have also highlighted the significant accumulation of iron in the PUT of patients with Parkinsonism syndromes and PD, using postmortem and MRI measurements, including conventional MRI, SWI, and QSM techniques [ 57 , 65 ].…”