Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder

“In humans, there have been a number of recent studies demonstrating enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastell…”

“Despite a widely varying clinical presentation, ASD is highly heritable, with studies demonstrating a concordance rate of 80–95% in monozygotic twins and 0–31% in dizygotic twins (Folstein and Rutter 1977; Ritvo et al. 1985; Bailey et al. 1995; Le Couteur et al. 1996; Taniai et al. 2008; Rosenberg et al. 2009).”

“In humans, there have been a number of recent studies demonstrating enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastell…”

“Similarly, although genome-wide copy number variation analyses have not highlighted OXTR (Glessner et al. 2009), a recent report described deletion of the region including OXTR, CAV3, and three neighboring genes in a single proband in one of 119 families (Gregory et al.”

“…enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastella et al. 2008b; Hurlemann et al. 2010).”

“OXT facilitates social recognition behavior (Ferguson et al. 2000) and modulates maternal behavior (Pedersen and Prange 1979; Kendrick et al.”

“1 (Wang et al. 2009), 5p15 (Weiss et al.”

“Intravenous or intranasal applications of OXT in youth (Guastella et al. 2010) and adult (Hollander et al. 2007; Hollander et al. 2003; Andari et al. 2010) cohorts with ASD generally improved various functions relevant to social behavior.”

“2010) and adult (Hollander et al. 2007; Hollander et al. 2003; Andari et al. 2010) cohorts with ASD generally improved various functions relevant to social behavior.”

“VP and OT systems have been implicated in sex-biased psychiatric disorders of social dysfunction, such as autism spectrum disorder and schizophrenia(Green et al., 2001; Wu et al., 2005; Jacob et al., 2007; Campbell et al., 2011; Miller et al., 2013; Di Napoli et al., 2014; Golimbet et al., 2014; Jobst et al., 2014).”

“…and alterations in: the gene that encodes the oxytocin receptor, OXTR, (Ebstein et al., 2009; Hammock and Levitt, 2006), in oxytocin receptors (Campbell et al., 2011; Liu et al., 2010; Skuse et al., 2014; Wermter et al., 2010; Wu et al., 2005), and in epigenetic mechanisms (Gregory et al.,…”

“…(p = .007) Patients carrying this haplotype showed nominally significant impairments in social interaction & communication compared to noncarriers Campbell et al. (2011)37 2333 (95% Caucasian) ASD probands & their families FBAT of 25 SNPs within OXTR Significant association between ASD & 3 SNPs…”

“The association of variation in intron 3 of the OXTR with psychological resources and depressive symptomatology is consistent with an emerging body of evidence associating variation in this region with similar psychological phenotypes (35, 50), psychological responses in experimental studies (33, 34, 37), and neural r…”

“Common polymorphisms, and epigenetic methylation of the promoter region of the oxytocin receptor gene are associated with risk for autism (Campbell et al. 2011; Lerer et al. 2008; Gregory et al. 2009).”

“There is growing evidence that allelic variation within the OXTR gene (including several single-nucleotide polymorphisms and halpotypes) has evolutionarily importance to social cognition and function, although functionally important alleles are unresolved (49-52).”

“Several genome-wide linkage studies have been used to analyze autistic populations, the largest of which found a linkage peak over the 3p25 chromosomal, the location of the OTR gene (Barrett et al., 1999; Campbell et al., 2011; Lauritsen et al., 2006; McCauley et al., 2005; Philippe et al., 1999; Ylisaukko-oja et al.,…”

“However, the two SNP do not seem to be in strong linkage equilibrium (Kawamura et al., 2010; Wermter et al., 2010; Campbell et al., 2011; Chen and Johnson, 2012; Johansson et al., 2012).”

“Genetic associations between ASD and the oxytocin receptor gene, and with the closely related vasopressin gene, have also been reported [170].”

“…the gene association studies implicating OXTR in autism (Wu et al, 2005; Jacob et al, 2007; Israel et al, 2008; Lerer et al, 2008; Liu et al, 2010; Campbell et al, 2011), and also that it may be difficult to detect the effect of OXTR alleles on autism risk (Tansey et al, 2010) without controlling…”

“With respect to social functioning in ASD, a clear association between OXTR genotype and social endophenotypes has been established in a large family-based study involving 2,333 individuals [68].”

“…the majority of reports, which primarily assess SNP associations with autistic or social behaviors, have not found associations with these SNPs (Campbell et al., 2011; Wu et al., 2012), and few studies have assessed interactions between these SNPs and early adversity (Loth et al., 2013; Myers…”

“…links between SNPs in OXTR and either autism spectrum disorder (ASD) diagnosis or ASD subdomains such as social interactions and communication (Campbell et al., 2011; Jacob et al., 2007; Liu et al., 2010; LoParo & Waldman, 2014; Walum et al., 2012; Wu et al., 2005; Ylisaukko-oja et al., 2006;…”

“Indeed, initial studies have linked variation in OXTR to susceptibility for mental disorders characterized by social deficits, such as ASD (Wu et al., 2005; Jacob et al., 2007; Lerer et al., 2008; Yrigollen et al., 2008; Gregory et al., 2009; Tansey et al., 2010; Wermter et al., 2010; Campbell et al., 2011), schizophr…”

“ASD is a neurodevelopmental disorder characterized by occurrence of a triad of behavioral symptoms: (1) deficits in social interaction, (2) impaired communication, and (3) ritualistic–repetitive behaviors; all typically detectable in early childhood but continuing throughout life (APA, 2000; Folstein and Rosen-Sheidle…”

“Notably, both syndromes have recently been linked to alterations in the OT system (Campbell et al. 2011 ; Dai et al. 2012 ; Pobbe et al. 2012).”

“…has also been tested in autismrelated studies; the C allele for rs1042778 has been found to be significantly associated with susceptibility to autistic spectrum disorders in children (Campbell et al. 2011; Lerer et al. 2008) although these findings did not survive correction for multiple analyses.”

“OXTR has been discussed as a candidate gene for autism spectrum vulnerability [60–68], but until to date only few studies have investigated variations of oxytocinergic system genes in schizophrenia [69–72].”

“This variant has previously been shown to be associated with a range of traits relevant to psychopathy, including prosociality, autism, interpersonal sensitivity, aggressive/antisocial behavior, and serum OXT levels (Campbell et al., 2011; Feldman et al., 2012; see Table 1).”

“[28] reported an association of oxytocin receptor genetic polymorphisms (rs2268493, rs1042778 and rs7632287) with social aspects of autism spectrum disorder.”

“In particular, associations between the OXTR gene and high-functioning autism could be demonstrated in several studies (Wu et al. 2005; Jacob et al. 2007; Yrigollen et al. 2008; Lerer et al. 2008; Liu et al. 2010; Wermter et al. 2010; Kelemenova et al. 2010; Campbell et al. 2011), but did not remain undisputed (Tansey…”

“Additional studies by Yrigollen et al. (2008) and Campbell et al. (2011) continued to build an association between the OT system and ASD.”

“Moreover, during the ovulation, the endogenous oxy activity is suppressed (Evans et al., 2003).”

“Campbell and colleagues found a correlation between rs7632287 and multiple domains of ASD (Campbell et al., 2011) and childhood social problems such as pair-bonding between mother and child (Walum et al., 2012).”

“Several studies investigating the relation between ASD and OXTR have found correlations between single nucleotide polymorphisms and ASD symptoms (Campbell et al., 2011; Ebstein et al., 2009; Jacob et al., 2007; Lerer et al., 2008; Liu et al., 2010; Walum et al., 2012; Wu et al., 2005; Ylisaukko-oja et al., 2006; Yrigo…”

“However, even in the largest of these studies to date, significant associations of these SNPs with ASD phenotypes have only exhibited a modest effect [Campbell et al., 2011].”

“2011 Family 1238 families Caucasian rs2268493, rs1042778, rs7632287 [43]”

“Findings from (epi-)genetic studies point to a possible involvement of the OT system in ASD pathophysiology, such as associations of variants of the OT receptor gene, OXTR, with autistic symptoms (e.g., Wu et al. 2005; Jacob et al. 2007; Campbell et al. 2011) and abnormalities in OXTR methylation in patients with ASD…”

“Subsequently, Campbell et al. (2011) used a narrow diagnosis of autism in an Autism Genetic Resource Exchange (AGRE) sample and found rs2268493T to be significantly associated with their diagnosis criteria.”

“The two most reported SNPs in OXTR that are associated with ASC are rs2254298 and rs53576 [23-25], while rs2268493 has been significantly [26] and nominally [27] associated with ASC in two different studies.”

“Other authors have associated depression and anxiety with the OXTR rs2254298 polymorphism in adults [23], and with autism in children [24].”

“The study was doubleblinded, i.e., the participants as well as the person performing the scanning were blinded to the genotype of the participants.”

“The endogenous OT systems are believed to be involved in the pathogenesis of ASD, based on results indicating low levels of plasma OT [34], alterations in OT peptide forms [35], sexually dimorphic patterns of OT associated with anxiety [36], dysregulation of OT signaling pathways [37] and common polymorphisms of the C…”

“(Campbell et al. 2011; Lerer et al. 2008).”

“For rs1042778 the G allele has been linked to ASD risk [10,62], and thus we compared 14 risk allele homozygotes (GG) to 17 non-risk allele homozygotes and heterozygotes (TT/TG).”

“Single nucleotide polymorphisms (SNPs) in the OXTR have been associated with autism in different populations [24–30], especially related to the social domain in autism [31, 32], although null-findings are also reported [33–35].”

“However, Liu et al. (2010) showed that the rs11131149 marker belonged to a haplotype block that was linked to ASD classification, and a separate investigation showed an association between this marker and depressive temperament (Kawamura et al. 2010).”

“SNP rs237889 was investigated in three independent studies [Campbell et al., 2011; Lerer et al., 2008; K. E. Tansey et al., 2010].”

“Genetic polymorphisms (SNPs) have been reported in OT and OTR human genes in association with social and pathological behaviors, such as ASD (Campbell et al. 2011; Aspe-Sanchez et al. 2015).”

“…(rs1042778, rs6770632, rs237885, rs4564970, rs1488467, rs53576, rs13316193) have been found to be related to aggression, CU behaviors, and/or behavior problems [Park et al., 2010; Campbell et al., 2011; Beitchman et al., 2012; Johansson et al., 2012a; Johansson et al., 2012b; Malik et al., 2012].”

“Furthermore, other SNPs on the oxytocin receptor gene have been associated with autism (Campbell et al., 2011; Jacob et al, 2007; Liu et al., 2010; Wu et al., 2005; Ylisaukko-oja et al, 2006).”

“Participants with the ‘TT’ genotype (n = 50), the identified risk allele (Kawamura et al., 2010; Campbell et al., 2011; Damiano et al., 2014), performed more poorly across these measures than those in the combined ‘CC + CT’ group (n = 23).”

“To date, several studies have found ASD-associated SNPs in the OXTR gene, which reside in introns (rs4564970 [41], rs237897 [25], rs53576 [23,24], rs2254298 [23-25], rs2268493 [42], rs7632287 [42], rs11720238 [41]), 3'-untranslated region (rs1042778) [42], and intergenic regions (rs7632287 and rs11720238) [41].”

“Nonetheless, genetic studies have mainly failed to associate the oxytocin gene with autism; however, several studies have reported an association with the oxytocin receptor gene (OXTR; NCBI Gene ID: 5021), although inconsistently [39-43].”

“…C. D. Guoynes et al. / Neuroscience xxx (2017) xxx–xxx et al., 2007; Gregory et al., 2009, Campbell et al., 2011, Teng et al., 2013; Alvares et al., 2017).”

“Several polymorphisms of OXTR have been associated with autism spectrum disorders and their associated deficits in social cognition (Lerer et al., 2008; Campbell et al., 2011; Harrison et al., 2015; LoParo and Waldman, 2015; Kranz et al., 2016) (but see Tansey et al.”

“…in the oxytocin receptor gene (OXTR) may be associated with diagnosis of ASD or with specific symptom domains related to social behavior [Campbell et al., 2011; Gregory et al., 2009; Jacob et al., 2007; Lerer INSAR260 Ceroni et al./CD38/BST1 deletion with autism and asthma et al., 2008;…”

“Given that several SNPs within OXTR correlate to pair-bonding in humans (Walum et al., 2012) and attachment security in infants (Chen et al., 2011), it is not surprising that they have also been implicated in ASD (Campbell et al., 2011; Jacob et al., 2007; Liu et al., 2010; Wu et al., 2005).”

“Further, two SNPs in OXTR, rs53576 (Wu et al., 2005) and rs2254298 (Lerer et al., 2008) are linked to autism, a disorder characterized by insensitivity to social cues (although there is some evidence of a non-association between these SNPs and autism, Campbell et al., 2011).”

“[68] identified three SNPs (rs2268493, rs1042778, rs7632287) nominally associated with autism.”

“associated with conditions involving reduced social bonding (Beitchman et al. 2012; Campbell et al. 2011; Di Napoli et al. 2014; Yrigollen et al. 2008), it may be that in the context of a group-based intervention, individuals homozygous for this allele were less sensitive to the effects of deviant peers and were less…”

“Polymorphisms in and near the 3′UTR is also involved in ASD risk [9,20,21].”

“5 kb downstream of OXTR and previous research demonstrating LD between the OXTR and CAV3 genes [Campbell et al., 2011], the current LDdiagram includes several of theCAV3 SNPs located near the OXTR gene genotyped in the current database.”

“18 As a result of these findings, synthetic oxytocin has emerged as a possible treatment for the social deficits associated with ASD.”

“…a large cohort of 2333 individuals with ASD has demonstrated an association between three markers implicated in ASD susceptibility, rs2268493, rs1042778, and rs7632287, further strengthening the hypothesis that functional polymorphisms of OXTR may contribute to ASD risk (Campbell et al., 2011).”

“Of these six studies, Guastella et al.’s (2014) RCT investigating the effects of a course of intranasal oxytocin on social behaviors in youths with ASDs, and Tachibana et al., were the only groups to investigate chronic administration of intranasal oxytocin over 2, and 6 month periods, respectively, although there was…”

“, 2011) and with the severity of communication deficits in autism (Jacob et al., 2007; Lerer et al., 2007; Campbell et al., 2011).”

“Three of the four were in high linkage disequilibrium (LD) and part of the same haplotype block (Campbell et al., 2011).”

“, 2011 (45) N/S N/S G: SS N/S G: SS N/S T: SS”

“In fact, approximately 3.7% of disease-associated variants in the NHGRI-EBI GWAS catalog localize to the Variants in the 3 ′ UTR may give rise to a decrease in mRNA stability, with lower mRNA levels and thereby protein abundance (Harrison et al., 2015; Campbell et al., 2011).”

“Because of the well-documented role of OXTR in social behavior, common genetic polymorphisms of this gene have been frequently reported in the ASD population (Campbell et al., 2011; Kranz et al., 2016; Liu et al., 2015), and have been the focus of several imaging genetics studies.”

“However, the statistical significance found in the family-based association test disappeared in the haplotype-based association tests [Campbell et al., 2011].”

“Lower levels of serum oxytocin in autistic patients [24] and association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of ASD [25] have been widely reported.”