Genetic Burden for Late-Life Neurodegenerative Disease and Its Association With Early-Life Lipids, Brain, Behavior, and Cognition

Background: Genetics play a significant role in the etiology of late-life neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. Part of the individual differences in risk for these diseases can be traced back decades before the onset of disease symptoms. Previous studies have shown evidence for plausible links of apolipoprotein E (APOE), the most important genetic marker for Alzheimer’s disease, with early-life cognition and neuroimaging markers. We aimed to assess whether genome-wide genetic burden for the aforementioned neurodegenerative diseases plays a role in early-life processes. Methods: We studied children from the Generation R Study, a prospective birth cohort. APOE genotypes and polygenic genetic burdens for Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia were obtained through genome-wide genotyping. Non-verbal intelligence was assessed through cognitive tests at the research center around the age of 6 years, and educational attainment through a national school performance test around the age of 11 years. The Child Behavior Checklist was administered around the age of 10 years, and data from the anxious/depressed, withdrawn/depressed, and the internalizing behavior problems scales were used. Children participated in a neuroimaging study when they were 10 years old, in which structural brain metrics were obtained. Lipid serum profiles, which may be influenced by APOE genotype, were assessed from venal blood obtained around the age of 6 years. The sample size per analysis varied between 1,641 and 3,650 children due to completeness of data. Results: We did not find evidence that APOE genotype or the polygenic scores impact on childhood nonverbal intelligence, educational attainment, internalizing behavior, and global brain structural measures including total brain volume and whole brain fractional anisotropy (all p > 0.05). Carriership of the APOE ε2 allele was associated with lower and APOE ε4 with higher low-density lipoprotein cholesterol concentrations when compared to APOE ε3/ε3 carriers. Conclusion: We found no evidence that genetic burden for late-life neurodegenerative diseases associates with early-life cognition, internalizing behavior, or global brain structure

Human brain anatomy reflects separable genetic and environmental components of socioeconomic status

Socioeconomic status (SES) correlates with brain structure, a relation of interest given the long-observed relations of SES to cognitive abilities and health. Yet, major questions remain open, in particular, the pattern of causality that underlies this relation. In an unprecedently large study, here, we assess genetic and environmental contributions to SES differences in neuroanatomy. We first establish robust SES–gray matter relations across a number of brain regions, cortical and subcortical. These regional correlates are parsed into predominantly genetic factors and those potentially due to the environment. We show that genetic effects are stronger in some areas (prefrontal cortex, insula) than others. In areas showing less genetic effect (cerebellum, lateral temporal), environmental factors are likely to be influential. Our results imply a complex interplay of genetic and environmental factors that influence the SES-brain relation and may eventually provide insights relevant to policy

주의력 결핍/과잉행동장애의 신경 아형과 임상적 연관성

학위논문(석사) -- 서울대학교대학원 : 자연과학대학 뇌인지과학과, 2023. 2. 차지욱.Attention-deficit/hyperactivity disorder (ADHD) is one of childhoods most common neurodevelopmental disorders, typically characterized by inattention, impulsivity, and hyperactivity. Despite previous studies exploring brain abnormalities in ADHD, these studies have frequently compared ADHD to a control group, potentially overlooking the heterogeneity within ADHD. Given the challenge posed by the varying symptoms of ADHD in making accurate diagnoses and providing effective treatments, it is essential to understand the heterogeneity in ADHD. To this end, this study uncovered the heterogeneity of the structural brain in ADHD using unsupervised clustering modeling. The clustering model revealed two distinct groups of ADHD. Then, this study investigated the relationship between the identified ADHD subgroups and clinical characteristics in prepubertal children (ages 9-10 years old; the Adolescent Brain Cognitive Development study). Both subgroups showed higher levels of ADHD symptoms compared to non-ADHD individuals, but ADHD-2 had higher internalizing mood and genome-polygenic scores (GPSs) for bipolar disorder, BMI, and risk tolerance. The brain profiles of each subgroup showed that ADHD-1 had reduced cortical measures with only a few regions, while ADHD-2 had overall brain volume reductions and decreased surface area. Additionally, the longitudinal analysis revealed different developmental patterns, with ADHD-1 showing reductions in cortical and subcortical volume and ADHD-2 showing reduced cortical thickness. The findings suggest the possibility of different brain pathologies within ADHD and the need for further understanding to inform diagnostic strategies. In conclusion, this study sheds light on the heterogeneity of ADHD and the underlying brain differences between subgroups, providing insights for improved diagnostic and therapeutic approaches in the future.주의력 결핍/과잉행동 장애 (ADHD)는 아동기 가장 흔한 신경 발달 장애 중 하나로, 주의력 결핍, 충동, 과잉 행동을 특징으로 한다. ADHD 뇌에서의 구조적, 기능적 이상성은 대조군과 비교하여 발견되어 왔다. 그러나 이러한 접근은 ADHD내에서의 개인 변동성과 이질성을 반영하는데 어려움이 있다. 이를 해결하기 위해 본 연구에서는 감독되지 않은 클러스터링 모델을 사용하여 ADHD 뇌에서의 이질성을 분리하고, 분리된 하위 그룹이 서로 다른 임상적 특성과 관련되는지를 조사하고자 했다. 연구 결과, 클러스터링 모델은 두 개의 ADHD 하위 그룹을 밝혀냈다. 두 개의 ADHD 하위 그룹은 대조군과 비교하여 높은 ADHD 증상 수준을 보였지만, 양극성 장애, BMI, 위험 감수의 유전 점수와 내재화 기분 증상에 대해서는 ADHD-2 하위 그룹에서만 유의미한 높은 점수를 보였다. 각 하위 그룹의 뇌 프로파일에서는, ADHD-1은 일부 영역에서만 피질 측정치가 감소한 반면, ADHD-2는 전반적인 뇌 부피 및 표면적의 감소를 보였다. 종단 연구 결과에서는 ADHD-1은 피질 및 피질하 부피의 감소, ADHD-2 는 피질 두께의 감소를 주요 특징으로 하는 등 뇌 발달 과정에서의 패턴 차이를 보였다. 종합하면, 본 연구는 ADHD 뇌의 이질성과 하위 집단 간의 임상적 지표 및 뇌에서의 차이를 조명하여, 향후 진단 및 치료 접근법에 대한 통찰력을 제공한다.1. INTRODUCTION 1 1.1. Background 1 1.1.1. Attention-deficit/hyperactivity disorder (ADHD) 1 1.1.1.1. ADHD in childhood 1 1.1.1.2. Structural brain abnormalities in ADHD 2 1.1.1.3. Genetic influences on ADHD 4 1.1.2. Heterogeneity in ADHD 5 1.2. Purpose of Research 6 2. Materials and Methods 7 2.1. Participants 7 2.2. ADHD 8 2.2.1. ADHD assessment 8 2.2.2. Comorbid disorders 9 2.2.3. Medication treatment 11 2.3. Neuropsychological measures 12 2.3.1. Cognitive measures 12 2.3.2. Behavioral measures 13 2.4. Missing data imputation 14 2.5. MRI data acquisition and processing 15 2.5.1. Structural magnetic resonance imaging (sMRI) 15 2.5.2. Diffusion magnetic resonance imaging (dMRI) 16 2.5.3. Quality assessment and control 16 2.6. Genetic data acquisition and processing 17 2.6.1. Genotype data 17 2.6.2. Genetic relatedness inference 18 2.6.3. Genome-wide polygenic scores (GPSs) 18 2.7. Dissecting the heterogeneity of the brain structure in ADHD 19 2.7.1. Dimensionality reduction 19 2.7.2. Agglomerative hierarchical clustering analysis 20 2.8. Relation to ADHD subgroups and neuropsychological measures 20 3. Results 22 3.1. Demographic characteristics 22 3.2. Dissecting the heterogeneity of the ADHD brain 24 3.3. Relation to ADHD subgroups and demographic, cognitive and behavioral measures 26 3.4. Relation to ADHD subgroups and GPS measures 31 3.5. Relation to ADHD subgroups and brain measures 34 3.6. Developmental changes of each ADHD subgroup 38 4. DISCUSSION 42 4.1. Summary 42 4.2. Implication and perspective 43 4.3. Limitations and future research direction 45 4.4. Conclusion 47 CONTRIBUTION 48 BIBLIOGRAPHY 49 국문초록 61 ACKNOWLEDGMENT 62석

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p <2.8 x 10(-6)) enrichment of associations at the gene level, forLOC388780(20p13; uncharacterized gene), and forVEPH1(3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (atp(T) = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase;p = 8 x 10(-13)), bipolar disorder (1.53[1.44; 1.63];p = 1 x 10(-43)), schizophrenia (1.36[1.28; 1.45];p = 4 x 10(-22)), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30];p = 3 x 10(-12)), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96];p = 5 x 10(-4)), educational attainment (0.86[0.82; 0.91];p = 2 x 10(-7)), and intelligence (0.72[0.68; 0.76];p = 9 x 10(-29)). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.Peer reviewe

Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization

Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. Polygenic risks for the two disorders were positively correlated (r=0.08, p=7.13×10-50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each polygenic risk score was associated with multivariate brain asymmetry after adjusting for sex, ASD r=0.03, p=2.17×10-9, schizophrenia r=0.04, p=2.61×10-11, but the multivariate patterns were mostly distinct for the two polygenic risks, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both polygenic risks were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risks for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits. Keywords: genome-wide association study; language; meta-analysis; readin

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits