Table V:
Imaging genetics studies in ASDs case-control samples and ASDs candidate genes studies in the healthy population (for selection of candidate genes see Table II).
| Gene | Polymorphism | Imaging modality | Imaging/cognitive phenotype | Genotype groups compared | Samples size (mean age in years) | Primary results (main effect of genotype) | Reference |
|---|---|---|---|---|---|---|---|
| CNTNAP2 | rs2710102 | fMRI | Reward-guided implicit learning task (fronto-striatal circuits) | C-allele carriers vs. non-risk-carriers | Discovery sample: 16 ASD (12.4) ‡ 16 HC (12.3) ‡ |
Non-risk group (collapsed across patients and controls): ↓ Activity in medial PFC during reward feedback processing; Risk group: ↑ long-range anterior-posterior connectivity between medial PFC, medial occipital, and ventral temporal cortices. | (Scott-Van Zeeland et al. 2010) |
| C-allele carriers vs. non-risk-carriers | Replication sample: 39 HC (13) | Non-risk-group: ↑ long-range anterior-posterior functional connectivity between mPFC, medial occipital, and ventral temporal cortices. | |||||
| rs2710102 | DTI | Whole-brain fiber tractography (graph theory analyses) | CC-carriers vs. CT/TT-carriers | 328 HC (23.4); twins from 189 families | CC-carriers: ↓ path length, ↑ small-worldness and global efficiency in whole-brain analyses, and ↑ eccentricity (maximum path length) in 60 of the 70 nodes in regional analyses. | (Dennis et al. 2011) | |
| rs7794745 | sMRI | WM and GM morphology | TT-carriers vs. AT/AA-carriers | 314 HC | TT-carriers: ↓ GM and WM volume in cerebellum, fusiform gyrus, occipital and frontal cortices. Male TT-carriers: ↓ GM in right frontal pole in right rostral fronto-occipital fasciculus. |
(Tan et al. 2010) | |
| DTI | WM integrity | TT-carriers: ↓ FA in cerebellum, fusiform gyrus, occipital and frontal cortices. Male TT-carriers: ↓FA in right rostral fronto-occipital fasciculus. Female TT-carriers: ↓ FA of anterior thalamic radiation. |
|||||
| rs7794745, rs2710102 | fMRI | Language task | Risk group (T- and C-allele) vs. non-risk group | 66 HC (20.54) | Risk group: ↑ activation in right IFG (Broca’s area homologue) and right lateral temporal cortex. | (Whalley et al. 2011) | |
| MET | rs1858830 | fMRI | Emotional faces task (n = 144), DMN functional connectivity (n = 71), WM structural connectivity (n = 84). | CC-carriers vs. CG-carriers vs. GG-carriers (non-risk) | 75 ASD (13.1) 87 HC (12.5) |
Risk genotype predicted wide-spread atypical fMRI activation (↑ amygdala and striatum) and deactivation patterns (↓ mainly posterior cingulate cortex) to social stimuli. Effects were more pronounced ASD group, especially within heterozygous risk group. | (Rudie et al. 2012) |
| rs-fMRI | Risk genotype: ↓ Functional and structural connectivity in temporo-parietal regions (within DMN) | ||||||
| DTI | Risk genotype: Altered WM integrity | ||||||
| rs1858830 | sMRI | Measures of cortical thickness (CT) development | CC-carriers vs. CG-carriers vs. GG-carriers | 222 HC (9-22) | C-carriers: ↓ CT (lowest in CC group) in superior and middle temporal gyri, ventral precentral and postcentral gyri, and anterior cingulate bilaterally, and in right frontopolar cortex. | (Hedrick et al. 2012) | |
| OXTR | rs2254298 | sMRI | Amygdala volume, TBV | GG-carriers vs. GA-carriers | 51 HC (13) † | GG-carriers: ↑ GM volume, ↓ amygdala volumes. VBM analysis revealed ↑ volume in region of dorsomedial ACC in GG-carriers and ↑ in posterior brainstem in G/A-carriers | (Furman et al. 2011) |
| sMRI (VBM) | Global brain measures (GM, WM, TBV) | AA- carriers vs. AG-carriers vs. GG-carriers | 135 HC (28.8)§ | Male A-allele carrier: ↓ GM volume in right insula (neuroanatomical correlate of ALTs). | (Saito et al. 2014) | ||
| rs1042778, rs2254298, rs237887, rs918316, rs2268493, rs53576, rs2268495 | sMRI | Amygdala and hippocampus volume, TBV | rs2254298: AA- carriers vs. AG-carriers vs. GG-carriers | 208 HC (33.9)§ | rs2254298: A-allele carriers: ↑ bilateral amygdala volume. Two 3-SNP haplotypes (including rs2254298 G-allele), showed associations with ↓ bilateral amygdala volume. | (Inoue et al. 2010) | |
| rs53576 | sMRI (VBM) | Global brain measures (GM, WM, TBV) | AA-carriers vs. GG/GA- carriers | 290 HC (23.7)§ | Female AA-carriers: ↓ amygdala volumes bilaterally (especially centromedial subregion, with a trend of allele-load-dependence) | (Wang et al. 2014) | |
| rs-fMRI | rsFC | ↓ Resting-state functional coupling between PFC and amygdala bilaterally (allele-load-dependent trend). | |||||
| rs-fMRI | Functional connectivity density (FCD) using a voxel-wise, data-driven approach | Male AA-carriers vs. male G-allele carriers | 270 HC (24.2)§ | FCD of hypothalamus exhibited main effect of genotype (↓FCD in male AA homozygotes). Gender-by-genotype interaction in resting-state FC (rsFC) between hypothalamic region and left dorsolateral PFC, but no main effect of genotype (↓ rsFC in male AA homozygotes). | (Wang et al. 2013) | ||
| sMRI (VBM) | Regional alterations in GM volume | GG-carriers vs. GA-carriers vs. AA-carriers | VBM: 212 HC (29.9) fMRI: 228 HC (31.9) (98 overlap) |
A-allele carriers: ↓ hypothalamus GM volume | (Tost et al. 2010) | ||
| fMRI | Face-matching task | A-allele carriers: ↓ amygdala activation, ↑ functional correlation of hypothalamus and amygdala during perceptual processing of facial emotion (specifically in male risk allele carriers lower levels of reward dependence predicted). | |||||
| 23-tagging SNPs (including rs7632287, rs237887, rs2268491, rs2254298, rs2268494) | fMRI | Animated angry faces task | rs237915: CC-carriers vs. CT/TT-carriers | 1445 HC (14.4) | CC-carriers: ↓ VS activity (related to more peer problems). | (Loth et al. 2014) | |
| rs53576 | fMRI | Others’ suffering task | GG-carriers vs. AA-carriers | 60 HC (20.2)§ | GG-carriers: hierarchical regression analyses revealed ↑ associations between interdependence and empathic neural responses in insula, amygdala, and superior temporal gyrus. | (Luo et al. 2015) | |
| fMRI | Emotional-valenced stimuli task | GG-carriers vs. AG/AA-carriers | 21 HC (34) | GG-carriers: ↑ functional connectivity between regions of interest. Bilateral amygdala and medial PFC show ↑ influence on other brain regions; bilateral pars opercularis, left amygdala, and left medial PFC are more receptive to activity in other brain regions. | (Verbeke et al. 2013) | ||
| rs1042778, rs2268493, rs237887 | fMRI | MID task | rs2268493: TT-carriers vs. CT/CC-carriers | 31 HC (23.6) | rs2268493 TT-carriers: ↓ Activation in mesolimbic reward circuitry (nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during anticipation of rewards but not during outcome phase. | (Damiano et al. 2014) | |
| rs53576, rs1042778 | fMRI | Mother-child interaction task | 3 genotype groups per SNP | 40 HC † | Both rs53576 and rs1042778 were associated with both positive parenting and hemodynamic responses to child stimuli in OFC, ACC, and hippocampus (rs53576 GG group showed lowest hemodynamic response). | (Michalska et al. 2014) | |
| rs2268498, rs180789, rs401015 | fMRI, doubleblind placebo-controlled crossover study | Social-emotional and gaze processing task; amygdala activation after intranasal oxytocin self-administration | rs401015: CT-carriers vs. TT-carriers | 55 HC (24.9) ‡ | rs401015 modulated right amygdala activity under influence of oxytocin (CT-carriers: ↑ amygdala activity). | (Montag et al. 2013) | |
| SLC6A4/5HTT | 5-HTTLPR | sMRI (VBM) | Total GM and WM volume | LL vs. LS vs. SS | 43 ASD (30) | No associations between total GM or WM volume and genotype. | (Raznahan et al. 2009) |
| sMRI (longitudinal) | Cerebral cortical and cerebellar GM and WM volume | SS vs. SL vs. LL | 44 ASD (3.4) ‡ | S-carriers: ↑ cortical and frontal lobe GM | (Wassink et al. 2007) | ||
| 5-HTTLPR, rs25531 | rs-fMRI | Functional connectivity | Low vs. high expressing | 54 ASD (13.7) 66 HC (14.5) |
Low expressing genotypes (SS, SLG, LGLG): ↑ posterior-anterior connectivity in ASD group (converse for HC). | (Wiggins et al. 2012) | |
| fMRI | Emotional faces task | Low vs. high expressing | 44 ASD (13.5) 65 HC (14.7) |
Low expressing genotypes (SS, SLG, LGLG): ↑ amygdala activation in ASD group. | (Wiggins et al. 2014) | ||
ACC = anterior cingulate cortex, ALT = autistic-like traits, CA = childhood adversity, CN = caudate nucleus, CT = cortical thickness, CV = cortical volume, DMN = default mode network, DTI = diffusion tensor imaging, GM = gray matter, FC = functional connectivity, FCD = functional connectivity density, HC = healthy control, IFG = inferior frontal gyrus, MID = monetary incentive delay task, mPFC = medial prefrontal cortex, OFC = orbitofrontal cortex, PFC = prefrontal cortex, ROI = region of interest, rsFC = resting-state functional connectivity, SA = surface area, SLE = stressful life events, sMRI = structural magnetic resonance imaging, STS = superior temporal sulcus, VBM = voxel-based morphometry, VS = ventral striatum, WM = white matter, TBV = total brain volume
†
only females
‡
only males
§
Asian sample
in gray only case-control studies; for SLC6A4 studies in healthy individuals see Tables IV and VI (ADHD).