Associations Between Early Maternal Depressive Symptom Trajectories And Toddlers’ Felt Security At 18 Months: Are Boys And Girls At Differential Risk?

The goal of this study was to evaluate whether there are sex differences in children’s vulnerability to caregiving risk, as indexed by trajectories of maternal depressive symptoms assessed from 2 to 18 monthsâ postpartum, and children’s rated attachment security in toddlerhood, adjusting for maternal social support and demographic risk. Analyses utilized longitudinal data collected for 182 African American motherâ child dyads from economically diverse backgrounds. Participants were recruited at the time of the child’s birth and followed to 18 monthsâ postpartum. Results of conditional latent growth models indicated that an increasing rate of change in level of maternal depressive symptoms over time negatively predicted toddlersâ felt attachment security. Higher social support was associated with decreasing levels of maternal depressive symptoms over time whereas higher demographic risk was associated with increasing levels of maternal depressive symptoms. A subsequent multigroup conditional latent growth model revealed that child sex moderated these associations. For male (but not female) children, a rapid increase in maternal depressive symptoms was associated with lower felt attachment security at 18 months. These findings suggest that boys, as compared to girls, may be more vulnerable to early caregiving risks such as maternal depression, with negative consequences for motherâ child attachment security in toddlerhood.RESUMENEl objetivo de este estudio fue evaluar si hay diferencias de sexo en la vulnerabilidad de los niños al riesgo de prestación de cuidado, como han indicado las trayectorias de síntomas depresivos maternos evaluadas de 2 a 18 meses después del parto, y el puntaje de la seguridad de afectividad de los niños en su temprana infancia, con ajustes basados en el apoyo social materno y el riesgo demográfico. Los análisis utilizaron información longitudinal recogida de 182 díadas de madreâ niño afroâ americanas de niveles económicamente diversos. Los participantes fueron reclutados al nacer el niño y se les dio seguimiento hasta los 18 meses después del parto. Los resultados de modelos de modelos de crecimiento latente condicionales indicaron que un incremento en el puntaje de cambio en el nivel de síntomas depresivos maternos a través del tiempo negativamente predijo la seguridad afectiva que los infantes sentían. Se asoció un más alto apoyo social con decrecientes niveles de síntomas depresivos maternos a través del tiempo, mientras que más altos riesgos demográficos se asociaron con un incrementos en los niveles de síntomas depresivos maternos. Un subsecuente modelo de crecimiento latente condicional reveló que el sexo del niño moderaba estas asociaciones. En el caso de niños varones (no así las niñas), se asoció un rápido incremento en síntomas depresivos maternos con más bajos niveles, a los 18 meses, de seguridad en la afectividad sentida. Estos resultados sugieren que los niños varones, comparados con las niñas, pudieran ser más vulnerables a los riesgos de un cuidado temprano tal como la depresión materna, con consecuencias negativas para la seguridad en la afectividad madreâ niño en la más temprana infancia.Rà SUMà Le but de cette étude était dâ évaluer s’il existe des différences entre les sexes dans la vulnérabilité des enfants au risque de la personne prenant soin d’eux, telle qu’elle est indexée par les trajectoires des symptômes dépressifs maternels évalués de 2 à 18 mois après la naissance, et la sécurité de l’attachement telle qu’elle est évaluée chez les enfants durant la petite enfance, s’ajustant au soutien social maternel et au risque démographique. Les analyses ont utilisé des données longitudinales recueillies pour 182 dyades mèresâ enfants noires américaines issues de milieux socioéconomiques divers. Les participants ont été recrutés au moment de la naissance de l’enfant et ont été suivis jusquâ à 18 mois après la naissance. Les résultats de modèles de croissance latents conditionnels ont indiqué qu’un taux croissant de changement dans le niveau des symptômes dépressifs maternels au fil du temps prédisait de manière négative la sécurité de l’attachement ressentie des jeunes enfants. Un soutien social plus élevé était lié à des niveaux décroissants de symptômes dépressifs maternels au fil du temps, alors qu’un risque démographique élevé était lié à des niveaux plus élevés de symptômes dépressifs maternels. Un modèle de croissance latente conditionnelle subséquente et multiâ groupe a révélé que le sexe de l’enfant modérait ces associations. Pour les enfants mâles (mais pas les enfants femelles) une augmentation rapide des symptômes dépressifs maternels était liée à une sécurité perçue de l’attachement plus basse à 18 mois. Ces résultats suggèrent que les garçons, comparés aux filles, peuvent être plus vulnérables aux risques liés à la personne prenant soin d’eux comme la dépression maternelle, avec des conséquences négatives pour la sécurité de l’attachement mèreâ enfant dans la petite enfance.ZUSAMMENFASSUNGDas Ziel dieser Studie war es, Geschlechtsunterschiede bei Kindern im Hinblick auf ihre Vulnerabilität bei Fürsorgerisiken zu evaluieren. Die Fürsorgerisiken wurden durch den Verlauf der mütterlichen depressiven Symptome von 2 bis 18 Monaten nach der Geburt indiziert, sowie durch die bewertete Bindungssicherheit der Kleinkinder. Dabei wurde für mütterliche soziale Unterstützung und demografische Risiken kontrolliert. Für die Analysen wurden Längsschnittdaten von 182 afroâ amerikanischen Mutterâ Kindâ Dyaden mit verschiedenen ökonomischen Hintergründen genutzt. Die Teilnehmer wurden zum Zeitpunkt der Geburt des Kindes rekrutiert und nach der Geburt für 18 Monate begleitet. Die Ergebnisse der konditionalen latenten Wachstumsmodelle zeigten, dass im Verlauf ansteigende mütterliche depressive Symptome mit der gefühlten Bindungssicherheit der Kleinkinder in einem negativen Vorhersagezusammenhang standen. Höhere soziale Unterstützung war mit einer Abnahme der mütterlichen depressiven Symptome im Verlauf der Zeit assoziiert, während ein höheres demografisches Risiko mit dem Anstieg der mütterlichen depressive Symptome assoziiert war. Ein nachfolgendes konditionales latentes Wachstumsmodell für multiple Gruppen zeigte, dass das Geschlecht des Kindes diese Assoziationen moderierte. Bei Jungen (jedoch nicht bei Mädchen) war eine rasche Zunahme der mütterlichen depressiven Symptome mit einer niedrigeren gefühlten Bindungssicherheit 18 Monate nach der Geburt assoziiert. Diese Ergebnisse deuten darauf hin, dass Jungen, verglichen mit Mädchen, hinsichtlich früher Fürsorgerisiken wie mütterlicher Depression vulnerabler sind, was wiederum mit negativen Folgen für die Bindungssicherheit zwischen Mutter und Kind im Kleinkindalter einhergehen kann.æ é ²ã ã ®ç  ç©¶ã ®ç ®ç ã ¯ã é¤ è ²ã ®ã ªã ¹ã ¯ã ¸ã ®å­ ã ©ã ã ®è å¼±æ §ã «æ §å·®ã ã ã ã ã ©ã ã ã è© ä¾¡ã ã ã 㠨㠧ã ã ã ã ã ã ¯ã å ºç £å¾ 2â ¼18ã æ ã «è© ä¾¡ã ã ã æ¯ è¦ªã ®æ ã ã ¤ç ç ¶ã ®çµ é 㠨幼å æ ã «è© å® ã ã ã ã ã ©ã ã ®æ ç ã ®å® å® æ §ã æ æ¨ ã «ã ã ¦ã æ¯ è¦ªã ®ç¤¾ä¼ ç æ ¯æ ´ã ¨äººå £çµ±è¨ å­¦ç 㠪㠹㠯㠫㠤ã ã ¦é ©å ã ã ã ã å æ ã ¯ã çµ æ¸ ç ã «å¤ æ§ ã ªè æ ¯ã æ ã ¤182çµ ã ®ã ¢ã ã ªã «ç³»ã ¢ã ¡ã ªã «äººã ®æ¯ å­ ã ã é ã ã ã ã ç¸¦æ ­ç ã ªã 㠼㠿ã å ©ç ¨ã ã ã ç  ç©¶å å  è ã ¯å­ ã ©ã ã ®å ºç æ ã «é ã ã ã ã ç £å¾ 18ã æ é 追跡ã ã ã ã æ ¡ä»¶ä» ã æ½ å ¨æ é ·ã ¢ã ã «ã ®çµ æ ã ã ã æ é çµ é ã «ã ã æ¯ è¦ªã ®æ ã ã ¤ç ç ¶ã ¬ã ã «ã ®å¤ å ç ã ®å¢ å  ã ¯ã å¹¼å ã «æ ã ã ã ã æ ç ã ®å® å® æ §ã ã ã ¬ã ã £ã ã «äº æ¸¬ã ã ã ã ¨ã 示ã ã ã ã ã ã é« ã ç¤¾ä¼ æ ¯æ ´ã ¯ã æ é çµ é ã «ã ã æ¯ è¦ªã ®æ ã ã ¤ç ç ¶ã ¬ã ã «ã ®ä½ ä¸ ã «é ¢é £ã ã ã ã ã ã ®ä¸ æ ¹ã ã é« ã äººå £çµ±è¨ å­¦ç ã ªã ¹ã ¯ã ¯æ¯ è¦ªã ®æ ã ã ¤ç ç ¶ã ¬ã ã «ã ®å¢ å  ã ¨é ¢é £ã ã ã ã ã ã «ç¶ ã å¤ ç¾¤æ ¡ä»¶ä» ã æ½ å ¨æ é ·ã ¢ã ã «ã ã ã å­ ã ©ã ã ®æ §å ¥ã ã ã ã ã ®é ¢é £ã ç·©å ã ã ã ç ·å 㠧㠯 (ã ã ã 女å 㠧㠯㠪ã ) ã æ ¥é ã «å¢ å¤§ã ã æ¯ è¦ªã ®æ ã ã ¤ç ç ¶ã ¯ã 18ã æ ã §æ ã ã ã ã æ ç ã ®å® å® æ §ã ®ä½ ã ã ¨é ¢é £ã ã ã ã ã ã ã ®çµ æ ã ã ã 女å ã «æ¯ ã ¹ã ¦ç ·å ã ¯ã æ¯ è¦ªã ®æ ã 㠤㠮ã ã ã ªæ ©æ ã ®é¤ è ²ã ªã ¹ã ¯ã «å¯¾ã ã ¦ã ã è 弱㠧ã ã ã å¹¼å æ ã ®æ¯ å­ ã ®æ ç ã ®å® å® æ §ã «ã ã ¬ã ã £ã ã ªçµ æ ã ã ã ã ã ã ¦ã ã ã æ è¦ æ ¬ç  ç©¶ç ç ®ç æ ¯è© ä¼°å ç«¥ç §é¡§é¢¨é ªç è å¼±æ §æ ¯å ¦å­ å ¨æ §å ¥å·®ç °, ä½ è æ ¹æ ç ¢å¾ 2è ³18å æ ç ç ¢å©¦æ 鬱ç ç ç è» è·¡, å å ç«¥å ¨å¹¼å æ ç é¡ å® ä¾ é å® å ¨æ è© ä¼°, ä¸¦èª¿æ ´æ¯ è¦ªç 社æ æ ¯æ å äººå £é¢¨é ªã ç  ç©¶å æ ä½¿ç ¨å¾ 182å ä¾ è ªç¶ æ¿ å¤ æ¨£å è æ ¯ç ç¾ å é æ´²è£ æ¯ å­ äº äººçµ å ç 縱å æ ¸æ ã å è è å ¨å­©å­ å ºç æ æ å , ç ¶å¾ è· é ²å °ç ¢å¾ 18å æ ã æ¢ ä»¶æ½ å ¨ç é ·æ¨¡å ç çµ æ 表æ , é ¨è æ é ç æ ¨ç§», æ¯ è¦ªæ 鬱ç ç ç å¢ å  ç , è² é ¢å °é  æ¸¬å¹¼å ç ä¾ é å® å ¨æ ã è¼ é« ç 社æ æ ¯æ è æ¯ è¦ªæ 鬱ç ç ç é ä½ ç ¸é , è è¼ é« ç äººå £é¢¨é ªè æ¯ è¦ªæ 鬱ç ç ç å¢ å  ç ¸é ã é ¨å¾ ç å¤ çµ æ¢ ä»¶æ½ å ¨ç é ·æ¨¡å å æ 顯示, å ç«¥æ §å ¥ç·©å é é ä¿ ã å° æ ¼ç ·å­© (ä½ ä¸ æ ¯å¥³å­©) , æ¯ è¦ªæ 鬱ç ç ç å¿«é å¢ å  è 18å æ æ è¼ ä½ ç ä¾ é å® å ¨æ æ é ã é äº ç  ç©¶çµ æ 表æ , è å¥³å­©ç ¸æ¯ , ç ·å­©å ¯è ½æ ´å®¹æ å å °æ ©æ ç §é¡§é¢¨é ª, ä¾ å¦ ç ¢å©¦æ 鬱ç , å° å¹¼å æ æ¯ å­ ä¾ é å® å ¨æ å¸¶ä¾ ç è² é ¢å½±é ¿ãPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135990/1/imhj21617.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135990/2/imhj21617_am.pd

Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n = 152) and 3, 311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P = 1.42 x 10(-12)),8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472;P = 3.41 x 10(-8)),and 2p22 at SOS1 (rs963731;P = 1.76 x 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22;rs1768208;P = 2.07 x 10(-7)) and MAPT H1c (17q21;rs242557;P = 7.91 x 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein)

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Funder: QingLan Research Project of Jiangsu for Outstanding Young TeachersFunder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical UniversityFunder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical UniversityAbstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population