Obesity gene NEGR1 associated with white matter integrity in healthy young adults

Obesity is a crucial public health issue in developed countries, with implications for cardiovascular and brain health as we age. A number of commonly-carried genetic variants are associated with obesity. Here we aim to see whether variants in obesity-associated genes - NEGR1, FTO, MTCH2, MC4R, LRRN6C, MAP2K5, FAIM2, SEC16B, ETV5, BDNF- AS, ATXN2L, ATP2A1, KCTD15, and TNN13K - are associated with white matter microstructural properties, assessed by high angular resolution diffusion imaging (HARDI) in young healthy adults between 20 and 30. years of age from the Queensland Twin Imaging study (QTIM). We began with a multi-locus approach testing how a number of common genetic risk factors for obesity at the single nucleotide polymorphism (SNP) level may jointly influence white matter integrity throughout the brain and found a wide spread genetic effect. Risk allele rs2815752 in NEGR1 was most associated with lower white matter integrity across a substantial portion of the brain. Across the area of significance in the bilateral posterior corona radiata, each additional copy of the risk allele was associated with a 2.2% lower average FA. This is the first study to find an association between an obesity risk gene and differences in white matter integrity. As our subjects were young and healthy, our results suggest that NEGR1 has effects on brain structure independent of its effect on obesity

The influence of body fat distribution on white matter integrity

Objective: Obesity has become a great health problem and increases the risk for cardiovascular and metabolic diseases as well as for cognitive impairments including brain alterations in gray and white matter structure and function. The differentiation of adipose tissue in visceral adipose tissue and subcutaneous adipose tissue was found to be greatly relevant due to its different composition and consequent potential for metabolic complications. Hence, the objective of this study was to investigate the relationship between body fat distribution, especially visceral and subcutaneous adipose tissue, and white matter integrity. Methods: Diffusion tensor imaging (DTI) of the brain and whole body magnetic resonance imaging were performed of 48 healthy young to middle-aged lean, overweight and obese participants. The collected data included participant’s sex, age, body mass index, total body volume, volume of total, subcutaneous and visceral adipose tissue, total intracranial volume and DTI data of the brain. By using a region-of-interest-based approach, the DTI parameters fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were analyzed and correlated with the body mass index, total adipose tissue, subcutaneous and visceral adipose tissue, controlling for age, sex, total intracranial volume and BMI. Results: We found significant positive correlations between visceral adipose tissue and mean diffusivity and radial diffusivity values in the hippocampal part of the left cingulum (p < 0.005, corrected for number of tested regions) and marginally significant positive correlations in the forceps major and hippocampal part of the right cingulum (p < 0.05). Subcutaneous and total adipose tissue did not show significant correlations with DTI parameters. Conclusion: Our DTI study contributed to the current knowledge of the relationship between visceral adipose tissue and white matter integrity. We conclude that increased visceral adipose tissue is associated with reduced white matter integrity in regions which are known to be important for emotional and cognitive functioning. Therefore we suggest that increased visceral adipose tissue may increase the risk for emotional and cognitive impairment. Still further longitudinal studies may determine causal impact of visceral adipose tissue and its clinical relevance

Altérations de l'intégrité de la matière blanche avec l'obésité

L'obésité est de plus en plus décrite comme une maladie chronique, complexe et progressive caractérisée par une accumulation anormale ou excessive de graisses corporelles nuisibles à la santé. En plus d'entraîner des altérations métaboliques, physiques et psychologiques importantes, cette condition est associée à une fonction cognitive altérée et une augmentation du risque de maladies neurodégénératives. Afin d'améliorer la prise en charge de l'obésité et de développer des interventions individualisées, il s'avère essentiel de mieux comprendre les facteurs impliqués dans sa physiopathologie, dont l'implication du cerveau. Cet organe joue un rôle central dans la régulation de l'appétit, la prise alimentaire et la prise de poids. Des études d'imagerie par résonnance magnétique (IRM) ont montré des altérations au niveau de la matière grise et de la matière blanche cérébrales avec l'obésité. Ces altérations pourraient être induites par les nombreux désordres métaboliques associés à l'obésité. À l'inverse, ces altérations pourraient rendre un individu vulnérable à l'environnement actuel, ce qui favoriserait le gain de poids. Pour mieux comprendre les mécanismes impliqués dans les altérations cérébrales observées avec l'obésité, il est important de mieux caractériser les différences cérébrales et d'examiner leurs implications dans le développement et la progression de l'obésité. Le Chapitre 1 de ce mémoire présente les résultats d'une méta-analyse visant à examiner les altérations de l'intégrité de la matière blanche dans un contexte d'obésité. Nous avons montré que les individus avec obésité sont caractérisés par une réduction de l'intégrité de la matière blanche dans la partie antérieure droite du corps calleux, un faisceau qui relie les régions frontales impliquées dans les processus cognitifs. Des études futures sont nécessaires pour valider les mécanismes et vérifier si les altérations cérébrales associées à l'obésité sont permanentes ou si elles peuvent être renversées à la suite d'une intervention visant à améliorer la santé cardiométabolique.Obesity is a chronic, complex and progressive disease characterized by an abnormal or excessive body fat accumulation that induces health issues. In addition to the well-known metabolic, physical and psychological alterations related to this disease, this condition is associated with impaired cognitive function and is a risk factor for neurodegenerative diseases. In order to improve the management of obesity and to develop individualized interventions, it is essential to better understand the factors involved in its physiopathology, including the involvement of the brain. This organ plays a central role in the regulation of appetite, food intake and weight gain. Magnetic resonance imaging (MRI) studies have shown alterations in the brain's grey matter and white matter with obesity. These brain abnormalities could be a consequence of the cardiometabolic alterations associated with obesity. Conversely, these brain differences might constitute risk factors for overeating and weight gain when individuals are exposed to favorable environmental or endogenous conditions. To better understand the mechanisms underlying brain alterations observed with obesity, it remains important to better characterize the brain differences and examine their implications in the development and progression of obesity. The Chapter 1 presents the results of a meta-analysis aiming to examine the most robust and reliable white matter integrity alterations with obesity. Our findings provide evidence that obesity is consistently associated with reduced white matter integrity in the genu of the corpus callosum, a region linking frontal areas involved in cognitive function. Future studies are needed to identify the mechanisms linking obesity with loss of white matter integrity and to verify if these brain alterations are permanent or whether they can be reversed after interventions targeting cardiometabolic health

Obez bireylerde transmembran protein 18 (tmem18) ve sinirsel büyüme regülatorü 1 (negr1) gen polimorfizmlerinin vücut kitle endeksi üzerine etkilerinin araştırılması

Obezite dünyanın birçok bölgesinde epidemik oranlara ulaşmış kompleks bir hastalıktır. Hastalık patogenezinde bireyin genetik altyapısı ve çevresel faktörler birlikte görev alır. Genetik çalışmalar, obezitede kalıtımın etkisi, belirli genlerin ve bunlara ait varyasyonların ırk, coğrafi bölge/ülke orjine bağlı ilişkilerini ortaya koymuştur. Son 10 yılda kullanıma giren Genom Ölçekli İlişkilendirme çalışmalarıyla (Genome Wide Association Studies, GWAS) vücut kütlesi ve obeziteyle ilişkili 50’den fazla aday gen tanımlanmıştır. Ancak söz konusu aday genlerin obeziteye ilişkin fonksiyonel mekanizmaları ve farklı populasyonlardaki verileri yetersizdir. Bu çalışmada, GWAS analizlerinde obeziteyle ilişkilendirilen NEGR1 geni rs2815752 ve TMEM18 geni rs6548238 polimorfizmleri ile Afyonkarahisar ilindeki obezite hastaları arasındaki ilişki araştırılmıştır. Çalışmamız bir vaka-kontrol çalışmasıdır. Polimorfizmler obezite teşhisi konmuş erkek(53)ve kadın (119) toplam 172 obez hastada (VKE ≥ 30 kg/m2, Ortalama VKE: 36,7 5,8) ve erkek(37)ve kadın (40) toplam 77 sağlıklı bireyde (VKE < 25 kg/m2, Ortalama VKE: 21,9 2,2) genotiplenmiştir. Genotiplendirme eş zamanlı PCR yöntemi ile yapılmıştır. Vücut kompozisyonu biyoelektrik impedans analizi ile belirlenmiştir. Çalışmamızda NEGR1 geni rs2815752 polimorfizmi genotip dağılımı olgu grubunda %53.5 AA, %37.2 AG, %9.3 GG ve kontrol grubunda %49.4 AA, %42.9 AG, %7.8 GG olarak bulundu. Obez olgu grubunda G allel frekansı %27.9 ve A allel frekansı %72.1, kontrol grubunda G alel frekansı %29.2 ve A allel frekansı %70.8 olarak belirlendi. TMEM18 geni rs6548238 polimorfizmi genotip dağılımı obez olgu grubunda %59.9 CC, %35.4 TC, %4.7 TT ve kontrol grubunda %63.6 CC, %31.2 TC, %5.2 TT olarak bulundu. Obez olgu grubunda T allel frekansı %22.4 ve C allel frekansı %77.6, kontrol grubunda T allel frekansı %21.9 ve C allel frekansı %79.2 olarak belirlendi. NEGR1 geni rs2815752 ve TMEM18 geni rs6548238 polimorfizmlerinin allel ve genotip frekansları açısından kontrol ve obez olgu grubu arasında fark bulunmadı. Rs2815752 polimorfizmi için obez olgularda antropometrik ölçüm ve vücut kompozisyon değerleri açısından fark bulunmadı. Rs6548238 polimorfizmi için obez olgularda antropometrik ölçüm ve vücut kompozisyon değerlerinden boy (p=0,020), vücut sıvı toplamı (p=0,017), vücut sıvı oranı (p=0,024), vücut yağ oranı (p=0,006) ve yağsız kitle (p=0,021) parametrelerinde fark bulundu. Sonuç olarak; çalışma grubumuzda obezite hastalığı ile NEGR1 geni rs2815752 ve TMEM18 geni rs6548238 polimorfizmleri arasında bir ilişki olmadığı belirlendi.Obesity is a complex disorder which has reached epidemic proportions in many parts of the world. It is collectively determined by genes and environmental factors. Genetic studies have demonstrated a high heritability for obesity and established associations of certain candidate genes and their variations with respect to race, geographical location/country of origin. The subsequent application of genome wide association studies (GWAS) in the last decade have identified more than 50 genetic loci associated with body mass and obesity. Hovewer, functional mechanisms and different ethnic backround datas of these loci are almost naive with regard to obesity. In this study, previously reported NEGR1 gene rs2815752 and TMEM18 gene rs6548238 GWAS single nucleotide polymorphisms (SNPs) were investigated for association in a sample of obesity patients who reside in Afyonkarahisar province. This was a case-control study. Polymorphisms were genotyped in 172 obese patients (men=53 and women=119) with a BMI ≥ 30 kg/m2 (Body Mass Index, mean:36,75,8) and 77 healthy controls (men=37 and women=40) with a BMI < 25 (mean: 21,92,2). Genotyping was performed by real-time polymerase chain reaction. Body composition was established with bio-electrical impedance analysis. According to obtained results, distribution of rs2815752 genotype frequencies in obese group were 53.5% for AA, 37.2% for AG and 9.3% for GG, in control group were 49.4% for AA, 42.9% for AG and 7.8% for GG. G and A allele frequencies in obese patients were 27.9% and 72.1% respectively, in controls 29.2% and 70.8% respectively. Distribution of rs6548238 genotype frequencies in obese group were 59.9% for CC, 35.4% for TC and 4.7% for TT, in control group were 63.6% for CC, 31.2% for TC and 5.2% for TT. T and C allele frequencies in obese patients were 22.4% and 77.6% respectively, in controls 21.9% and 79.2% respectively. There were no significant differences between obese and controls in terms of allele and genotype frequencies of NEGR1 gene rs2815752 and TMEM18 gene rs6548238 polymorphisms. Also there were no significant differences among obese patients with regard to anthropometric measurements and body composition parameters for rs2815752 polymorphism. However, several significant differences were found for rs6548238 polymorphism with regard to anthropometric measurements and body composition. These were height (p=0.020), body fluid amount (p=0.017), body fluid percentage (p=0.024), body fat percentage (p=0.006) and fat-free mass (p=0.021). Consequently, there is no association with obesity in our study group for NEGR1 gene rs2815752 and TMEM18 gene rs6548238 polymorphisms.Bu tez Afyon Kocatepe Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi tarafından BAP 15SAĞ.11 proje numarası ile desteklenmiştir

Neuropsühhiaatriliste endofenotüüpide seos IgLON adhesioonimolekulidega hiire ajus

Väitekirja elektrooniline versioon ei sisalda publikatsioonePsühhiaatriliste häirete multifaktoriaalse patogeneesi mõistmine on suur väljakutse. Neuropsühhiaatriliste häirete modelleerimine loommudelites annab võimaluse uurida, kuidas närviringete düsfunktsionaalsus põhjustab patoloogiliste fenotüüpide avaldumist. Erinevad ülegenoomsed assotsiatsiooniuuringud (GWAS) ning ekspressiooniuuringud on näidanud IgLON perekonda kuuluvate adhesioonimolekulide (Lsamp, Ntm, Opcml, Negr1, IgLON 5) seost inimese neuropsühhiaatriliste häiretega ning käitumiskatsed Lsamp ja Ntm puudulike hiirtega on näidanud IgLON molekulide osalust emotsionaalse ja sotsiaalse käitumise kujunemises. Funktsionaalsed uuringud on näidanud, et IgLON valgud osalevad närviringete kujunemisel ja toimimisel nii arenevas kui ka täiskasvanud ajus. On teada, et tsütoskeleti dünaamilised ümberkorraldused arenevates neuronites on aluseks neuraalsete ringete kujunemisele, kuid IgLON perekonna molekulide roll arenevate neuronite tsütoskeleti reguleerimises on olnud siiani teadmata. Käesoleva töö eesmärk oli selgitada Lsamp ja Ntm vaheliste vastastoimete ja Negr1 mõju aju struktuurile ja funktsioonidele, kasutades vastavate geenide suhtes mutantseid hiiremudeleid. Analüüsisime neuropsühhiaatriliste häiretega seotud morfoloogilisi, anatoomilisi ja käitumuslikke parameetreid Lsamp−/−, Ntm−/−, Lsamp−/−Ntm−/− ja Negr1−/− hiirtes. Mitmetasandiline lähenemine aitab selgitada, kuidas aju struktuursed kõrvalekalded mõjutavad käitumist. Näitasime, et Lsamp ja Ntm mõjutavad varajast neuriitide väljakasvu ja rakkude jagunemist ning apoptoosi teineteisest sõltuvalt ning samasugused vastasmõjud on jälgitavad ka mutanthiirte käitumuslikes reaktsioonides. Leidsime, et Negr1−/− hiirtel on kõrvalekalded neuritogeneesis, neuroanatoomias ja et nende hipokampuses on vähem inhibitoorseid neuroneid, mis võivad olla sellele hiireliinile iseloomuliku puuduliku sotsiaalse ja tunnetusliku käitumise põhjuseks. Lisaks näitavad käesoleva väitekirja tulemused, et IgLON adhesioonimolekulide toime võib olla sõltumatu rakkudevahelisest adhesioonist. Meie uurimistulemused aitavad mõista, kuidas IgLON adhesioonivalgud, mille geenipiirkonnad on olulised riskilookused paljudele psühhiaatrilistele häiretele, reguleerivad närviringete kujunemist, mõjutades neuronite morfoloogiat ja omadusi ning aju anatoomiat. Neid neuronaalseid muutusi, mis seostuvad muutustega käitumises, võib vaadata kui psühhiaatriliste häiretega seotud endofenotüüpe. Oleme näidanud erinevate IgLON puudulikkusega hiiremudelite sobivust psühhiaatriliste häirete modelleerimiseks ning nende mudelite edasine uurimine aitab neuropsühhiaatriliste häirete kujunemist paremini mõista.Understanding the multifactorial pathogenesis of neuropsychiatric disorders is a considerable challenge. Modelling neuropsychiatric disorders in animals provides us a medium to explore the endophenotypes of these disorders to understand how malfunctioning neuronal circuits manifest as pathological phenotypes. Several genome wide association studies (GWAS) and expression studies have linked IgLON superfamily of cell adhesion molecules (Lsamp, Ntm, Opcml, Negr1, IgLON 5) with neuropsychiatric disorders in humans. Analyses of Lsamp and Ntm deficient mice have shown that these genes are involved in patterning of emotional and social behavior. During development, IgLON cell adhesion molecules assist fundamental neuronal communication and the establishment of circuits through morphological changes in the developing neurons, driven by dynamic rearrangements of the cytoskeleton. The role of IgLON molecules in cytoskeletal regulation during development has remained unknown until now. The goal of the present study was to address the effect of interaction between Lsamp and Ntm and the impact of Negr1 on brain structure and function using deletional mouse models. We studied morphological, anatomical and behavioral parameters related to endophenotypes of neuropsychiatric disorders in Lsamp−/−, Ntm−/−, Lsamp−/−Ntm−/− and Negr1−/− mice. This approach allowed us to gain insight into how structural alterations in the brain can influence manifestations at the behavioral level. We showed that Lsamp and Ntm adhesion molecules interact mutually with each other to coordinate early neurite sprouting, proliferation and apoptosis, which manifest at behavior in adult. Our observation on Negr1−/− mice revealed alterations in neuritogenesis and neuroanatomy, and reduced number of inhibitory interneurons in the hippocampus that may underlie the aberrant social and cognitive behavior. Additionally, we propose that the function of IgLON molecules can exhibit through cell autonomous mechanisms during initiation of neurite sprouting independent of cell-adhesion functions. Our findings expand the understanding of how IgLONs, which are candidate genes for a wide spectrum of psychiatric disorders, are involved in the regulation of neuronal circuits at the level of neuronal morphology and neuronal properties, and how they consequently impact the structural anatomy of the brain. These neuronal alterations that manifest as behavioral alterations can be viewed as endophenotypes of neuropsychiatric disorders. We have demonstrated the suitability of IgLON-deficient mice as models for psychiatric disorders. The future investigation of these models enables better understanding of the pathogenesis and treatment of neuropsychiatric disordershttps://www.ester.ee/record=b524318

Arenguline lähenemine emotsionaalse käitumisega seotud geenide Wfs1 ja Lsampʼi funktsiooni uurimisel

Väitekirja elektrooniline versioon ei sisalda publikatsioonePsühhiaatriliste häirete kujunemises mängib olulist rolli aju areng. Geenid, mis osalevad emotsioonidega seotud ajupiirkondade arengus ja funktsioneerimises, on olulised psühhiaatriliste häirete seisukohalt. Wfs1 ja Lsamp geenid osalevad hirmu- ja ärevuskäitumise regulatsioonis. Wfs1 (Wolframi sündroom 1), nagu nimigi ütleb, on seotud samanimelise haruldase sündroomiga, mille sümptomid on diabetes insipidus, diabetes mellitus, nägemisnärvi kärbumine ja sensorineuraalne kurtus, sageli kaasnevad ka psühhiaatrilised häired. Wfs1 valk mängib olulist rolli insuliini sekretsioonis ja pankrease β-rakkude ellujäämise tagamises, selle funktsioonist ajus on vähem teada. Lsamp (limbilise süsteemiga seotud membraanivalk) osaleb neuriitide väljakasvu, aksonite sihtmärgini jõudmise ja sünaptogeneesi reguleerimises. Lsamp geenil on kaks evolutsiooniliselt konserveerunud alternatiivset esimest eksonit koos eraldi promootoritega, sellise struktuuri funktsionaalne tähtsus on teadmata. Nii Wfs1 kui Lsamp geeni puhul on näidatud kindlate alleelide seotust meeleolu- ja ärevushäirete, skisofreenia ja suitsidaalsusega. Enda doktoritöös uurisin Wfs1 ja Lsamp`i funktsiooni arengulisest vaatevinklist. Selgus, et Wfs1 ekspressioon on evolutsiooniliselt konserveerunud dopamiinergilist sisendit saavates ajupiirkondades, ning et Wfs1 suhtes puudulike hiirte hipokampuses on D1-tüüpi dopamiini retseptorite hulk suurenenud. Arengu käigus ekspresseerus Wfs1 ajutiselt paljudes ajupiirkondades; see laialdane ekspressioon polnud seotud arengulise endoplasmaatilise retiikulumi stressi vastuse regulatsiooniga, mis on üks Wfs1 põhilisi funktsioone täiskasvanud organismis. Lsamp`i puhul näitasime, et selle alternatiivsed promootorid on aktiivsed erinevate funktsioonidega ajupiirkondades: 1a-promootor on põhiline limbilises süsteemis, samas kui 1b-promootori aktiivsus piiritleb sensoorseid juhteteid. Lsamp`i promootorite aktiivsus hiirte hipokampuses, ventraalses striatumis ja temporaalsagaras korreleerus sotsiaalse- ja ärevusega seotud käitumise näitajatega. Saadud tulemused aitavad paremini mõista Wfs1 ja Lsamp`i rolli psühhiaatriliste häirete väljakujunemises ning näitavad suunda edasisteks uuringuteks.Genes that are involved in the development and functioning of the emotional circuits of the brain are highly susceptible targets in psychiatric diseases. Wfs1 and Lsamp, two genes studied in the present thesis, are both involved in the regulation of anxiety- and fear-related behaviour in the adult brain. Wfs1 (Wolfram syndrome 1) is a causative gene for Wolfram syndrome, a rare genetic disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness. Often, the core symptoms are accompanied by psychiatric manifestations. Wfs1 is important for the survival and functioning of pancreatic β-cells, its roles in the nervous system are not well understood. Lsamp (Limbic system associated membrane protein) is involved in regulating neurite outgrowth, axon targeting and synaptogenesis in the limbic system. Lsamp has two alternative first exons with separate promoters, the role of this conserved gene structure is unknown. Allelic variants of both, Wfs1 and Lsamp, are associated with depression, anxiety disorders, bipolar disorder, schizophrenia and suicidality. We took advantage of the neurodevelopmental approach to study the functions of Wfs1 and Lsamp in the brain. Wfs1 showed evolutionarily conserved expression in the dopaminoceptive brain regions. Relating to this, Wfs1-deficient mice had increased number of D1-type dopamine receptor ligand binding sites in the hippocampi compared to wild-type mice. During the development, Wfs1 was transiently expressed in many brain regions. The widespread expression of Wfs1 in early postnatal mouse brain was not involved in the regulation of developmental endoplasmic reticulum stress, which has previously been shown to be one of the main functions of Wfs1 in the adult organism. The activity pattern of the two alternative promoters of Lsamp was complementary in the mouse brain: 1a promoter was prevailing in the limbic-related structures, while the activity of 1b promoter mainly delineated sensory pathways. The activity of Lsamp promoters in the hippocampus, ventral striatum and temporal lobe correlated with measures of anxiety and social behaviour of mice. The present results help to understand the role of Wfs1 and Lsamp in the context of psychiatric diseases and point direction for further research

INVESTIGATING THE GENETICS OF MICROSTRUCTURE OF THE CORPUS CALLOSUM IN THE AGEING BRAIN

Abstract: Age-related atrophy of the corpus callosum (CC) has been associated with cognitive impairment and neurodegenerative disease. To date, there is limited knowledge about the role genetics plays in age-related microstructural changes of CC. The current study sought to examine the role of genetic factors on the microstructure of CC in older individuals. Heritability, genetic correlation analyses and a genome-wide search for SNPs associated with the microstructural integrity of CC were undertaken. Brain imaging scans were collected from two studies of community-dwelling older adults the Older Australian Twins Study (OATS) and the Sydney Memory and Ageing Study (MAS). Diffusion tensor imaging (DTI) measures were estimated for the whole CC as well as for five subregions. Parcellation of the CC was performed using Analyze® software. Heritability analyses for CC DTI measures were undertaken in 284 healthy older twins (66% female; 79 MZ and 63 DZ pairs) from OATS (mean age = 69.82, SD=4.76 years). Heritability and genetic correlation analyses were undertaken using the SOLAR software package. Genome-wide association studies (GWAS) for CC DTI measures were undertaken in MAS and replication performed in OATS. Heritability (h2) analysis for the whole CC, indicated significant h2 for fractional anisotropy (FA) (h2=0.56), mean diffusivity (MD) (h2=0.52), radial diffusivity (RD) (h2=0.49) and axial diffusivity (AD) (h2=0.37). Bivariate genetic correlation analyses were also performed between whole CC DTI measures. Across the DTI measures for the whole CC, MD and RD shared 84% of the common genetic variance, followed by MD- AD (77%), FA - RD (52%), RD- AD (37%) and FA MD (11%). The GWAS did not identify any significant SNPs nor were any of the suggestive SNPs replicated in OATS. In addition, candidate CC DTI SNPs were not associated with CC DTI measures. These findings suggest that the CC white matter microstructure in older adults is generally under moderate genetic control. There was also evidence of shared genetic factors between all four CC DTI measures. This study did not identify any significant SNPs associated with CC DTI measures in the GWAS analysis. This work suggests larger genetic association studies may be required to find CC-DTI associated SNPs