R.K. Moyzis’s research while affiliated with University of California, Irvine and other places

To investigate the association of attention‐deficit/hyperactivity disorder (ADHD) with the 48‐base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64–1.3). The p ‐value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12–0.92) and p = 0.03. Because our study used TDT analysis, we meta‐analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80–1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta‐analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57–1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation.

Background Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component, characterized by persistent symptoms of inattention, hyperactivity, and/or impulsivity. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 whole-genome significant risk loci in the European population. However, genetic risk factors for ADHD are less well-characterized in the Asian population, especially for rare variants. Methods Here, we present an analysis of common and rare variant contributions to ADHD in a Hong Kong sample comprising 279 cases and 432 controls, who were genotyped using the Illumina Infinium Global Screening Array. Results We identified 41 potential genomic risk loci with a suggestive association ( p < 1e ⁻⁴ ), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Furthermore, tissue enrichment analysis implicated the involvement of the cerebellum. POC1B , a gene previously found in a genome-wide significant locus of ADHD in the European population, was replicated in the current study, potentially implicating a trans-ancestral effect in ADHD. In addition, an accumulation of ADHD common-variant risks found in European ancestry samples was found to be significantly associated with ADHD in the current study. At the polygenic level, we also discovered a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks, which is consistent with the neural pathophysiology for ADHD. In rare variant analyses, we discovered that ADHD cases carried an elevated load of rare damaging variants in TEP1 , MTMR10 , DBH , TBCC, and ANO1 . ADHD genetic risk was associated with immune processes, demonstrated in both common and rare variant analyses. Conclusions These findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective.

What might explain our instinctual attraction to certain individuals, aside from visible factors such as appear-ance? We examined possible biologically-driven selection for immunology genes, specifically preferences for Major Histocompatibility Complex (MHC)-dissimilarity, through the ecologically-valid method of speed-dating. Two-hundred-and-sixty-two single Asian Americans went on speed-dates (N observations = 2215) with participants of the other sex, making second date offers and rating each other on measures of mate desirability, facial attractiveness, and body scent attractiveness. Using a single nucleotide polymorphism (SNP) analysis, women, but not men, showed preferences for speed-dating partners based on MHC-complementarity. The direction of findings varied by single nucleotide polymorphism (SNP), such that SNPs closer to the major HLA (Human Leukocyte Antigen) genes supported dissimilarity preferences, whereas those farther away supported similarity preferences. The relative effects of MHC-based measures in comparison to an array of behavioral predictors were examined via random forests. Results indicated that for both men and women, the importance of MHC-based indices was comparable to that of a partner's self-reported personality attributes in predicting second date offers.

In this article, we attempt to integrate recent advances in our understanding of the relations between culture and genes into an emerging field—cultural genomics—and discuss its promises and theoretical and methodological challenges. We first provide a brief review of previous conceptualizations about the relations between culture and genes and then argue that recent advances in molecular evolution research has allowed us to reframe the discussion away from parallel genetic and cultural evolution to focus on the interactions between the two. After outlining the key issues involved in cultural genomics (unit of analysis, timescale, mechanisms, and direction of influence), we provide examples of research for the different levels of interactions between culture and genes. We then discuss ideological, theoretical, and methodological challenges in cultural genomics and propose tentative solutions.

The CHAT gene encodes choline acetyltransferase, which is an enzyme responsible for the biosynthesis of the neurotransmitter acetylcholine in the brain. This study collected structural MRI, genetic, and behavioral data from 324 healthy Chinese adults, and examined the associations between CHAT genetic variants, parahippocampal and hippocampal structure, and short-term memory span. After controlling for intracranial volume, sex, and age, CHAT SNP rs12246528 had the strongest association with parahippocampal structure, with the A allele being linked to smaller volume, surface area, and thickness. SNP rs1917814 had the strongest association with hippocampal volume, with the T allele being linked to larger hippocampal volume. After controlling for sex and age, CHAT rs3729496 had the strongest association with memory span, with the T allele being associated with a greater memory span. Finally, the left parahippocampal gyrus surface area was positively associated with memory span. This study provides the first evidence for the involvement of the CHAT gene in parahippocampal and hippocampal structures and memory span in healthy Chinese adults. The choline acetyltransferase (CHAT) gene is associated with parahippocampal and hippocampal structure and short-term memory span.

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Dataset for this study. (XLS)

The CNTNAP2 (contactin associated protein-like 2) gene, highly expressed in the human prefrontal cortex, has been linked with autism and language impairment. Potential relationships between CNTNAP2, dorsolateral prefrontal cortex (DLPFC), and cognition have been suggested by previous clinical studies, but have not been directly examined in the same study. The current study collected structural MRI, genetic, and behavioral data in 317 healthy Chinese adults, and examined associations between CNTNAP2 variants, DLPFC, and cognitive performance (measured by the Stroop task). After controlling for intracranial volume, sex, and age, the CNTNAP2 genetic polymorphism at SNP rs7809486 had the strongest association with bilateral DLPFC volume (p = 0.00015 and 0.00014 for left and right DLPFC volumes, respectively), with GG homozygotes having greater bilateral DLPFC volumes and surface areas than the other genotypes. Furthermore, TT homozygotes of CNTNAP2 rs4726946 (a nearby SNP that had moderate linkage disequilibrium with rs7809486) had greater left DLPFC volume and surface area, and better cognitive performance than the other genotypes. Subjects with greater left DLPFC surface area had better cognitive performance. Importantly, the left DLPFC surface area mediated the association between the CNTNAP2 rs4726946 genotype and cognitive performance. This study provides the first evidence for associations among the CNTNAP2 gene, left DLPFC structure, and cognitive control.