Gender-specific Associations of the Brain-derived Neurotrophic FactorVal66MetPolymorphism with Neurocognitive and Clinical Features in Schizophrenia

Abstract

ObjectiveTo explore associations of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with cognitive functioning and psychopathology in patients with schizophrenia.MethodsWe included 133 subjects meeting the DSM-IV criteria for schizophrenia who were in the post-acute stage of the disease. BDNF Val66Met genotypes were identified via polymerase chain reaction. The computerized neurocognitive function battery, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Social and Occupational Functioning Scale (SOFAS), and the Subjective Well-being under Neuroleptic Treatment (SWN-K) were administered. Gender-stratified sub-analysis was also conducted to identify gender-specific patterns in the findings.ResultsIn male patients, no significant difference in any measure by BDNF genotype was evident. In female patients, scores on the CDSS and total PANSS and all subscales were significantly higher in valine (Val) carriers. In addition, scores on the SOFAS and SWN-K were significantly lower in Val carriers. In terms of neurocognitive measures, female patients with the Val allele had significantly poorer reaction times and fewer correct responses on the Continuous Performance Test (CPT) and the Trail Making Test (Parts A and B). After adjustment of PANSS total scores and log-transformed CDSS scores, CPT outcomes were significantly poorer in female patients with than in those without the Val allele.ConclusionGender-specific associations of the Val allele with poor neurocognitive function and more severe psychopathology were evident. Further studies are required to explore the mechanisms of these differences and the potential utility of the BDNF genotype as a predictor of outcome in patients with schizophrenia.

Impact of brain‐derived neurotrophic factor genetic polymorphism on cognition: A systematic review

“…The included studies examined genetic association with neurocognition in healthy patients and other disease states. In total, 40 of the 82 reviewed studies (48.8%) (Aas et al., ; Alfimova, Korovaitseva, Lezheiko, & Golimbet, ; Altmann et al., ; Avgan et al., ; Barbey et al., ; Canivet et al., ; Cao et al., ; De Beaumont, Fiocco, Quesnel, Lupien, & Poirier, ; Egan, Kojima, & Callicott, ; Freundlieb et al., ; Gajewski, Hengstler, Golka, Falkenstein, & Beste, ; Gong et al., ; Gonzalez et al., ; Gonzalez‐Giraldo et al., ; Gosselin et al., ; Ho, Andreasen, Dawson, & Wassink, ; Huang et al., ; Jasinska et al., ; Kim et al., ; Lamb, Thompson, McKay, Waldie, & Kirk, ; Lee, Baek, & Kim, ; Lim et al., , ; Miyajima et al., ; McAllister et al., ; Nagata, Shinagawa, Nukariya, Yamada, & Nakayama, ; Narayanan et al., ; Ng et al., ; Raz, Rodrigue, Kennedy, & Land, ; Richter‐Schmidinger et al., ; Rybakowski, Borkoswka, Czerski, Skibinska, & Hauser, ; Rybakowski et al., ; Schofield et al., ; Szabo et al., ; Tan et al., ; Tukel et al., ; van der Kolk et al., ; Yin, Hou, Wang, Sui, & Yuan, ; Yogeetha et al., ; Zhang et al., ) reported a significant association between Val66Met polymorphism and the neurocognitive domains of interest.…”

“…A total of 23 studies evaluated the association between the BDNF polymorphism and the attention/concentration domain (Alfimova et al., ; Cherubin et al., ; da Rocha, Malloy‐Diniz, Lage, & Correa, ; Dennis et al., ; Freundlieb et al., ; Freundlieb et al., ; Gatt et al., ; Ho et al., ; Huang et al., ; Kim et al., ; Lim et al., ; Lin et al., ; Mezquida et al., ; Narayanan et al., ; Oroszi et al., ; Schofield et al., ; Swardfager et al., ; Szabo et al., ; Thow, Summers, Summers, Saunders, & Vickers, ; Tukel et al., ; Ward et al., ; Yu et al., ; Zhang et al., ). Ten of these studies focused on healthy subjects (Alfimova et al., ; Cherubin et al., ; Dennis et al., ; Freundlieb et al., , ; Gatt et al., ; Huang et al., ; Lim et al., ; Schofield et al., ; Ward et al., ), and the rest evaluated samples of different disease states such as Alzheimer’s disease ( n = 1) (Lin et al., ), cardiovascular diseases ( n = 2) (Swardfager et al., ; Szabo et al., ), obsessive‐compulsive disorder ( n = 2) (da Rocha et al., ; Tukel et al., ), schizophrenia ( n = 5) (Ho et al., ; Kim et al., ; Mezquida et al., ; Zhang et al., , ), traumatic brain injury ( n = 2) (Narayanan et al., ; Yu et al., ), and systemic lupus erythematous ( n = 1) (Oroszi et al., ).…”

“…Among the reviewed studies, four studies (17.4%) (Kim et al., ; Narayanan et al., ; Szabo et al., ; Zhang et al., ) observed significant positive association between BDNF Val66Met polymorphism and the attention/concentration domain. In a study conducted in patients with mild traumatic brain injury, Val/Val homozygotes were reported to perform better in domains of attention/concentration over time (Narayanan et al., ).…”

“…Conversely, Met carriers were reported to perform better than Val/Val homozygotes in attention/concentration domain in another study focusing on elderly population with cardiovascular diseases (Szabo et al., ). In studies conducted in the schizophrenic population, one reported that Val/Val homozygotes had better attention performance than carriers of Met/Met homozygotes (Zhang et al., ), while another study reported the association of Val allele with poorer neurocognitive function in the attention/concentration domain (Kim et al., ).…”

“…Forty‐seven relevant studies were identified within the executive function domain. Twenty studies evaluated on healthy subjects (Alfimova et al., ; Cherubin et al., ; Dennis et al., ; De Beaumont et al., ; Erickson et al., ; Freundlieb et al., ; Freundlieb et al., ; Gong et al., ; Gajewski et al., ; Ghisletta et al., ; Gonzalez et al., ; Harris et al., ; Huang et al., ; Lim et al., ; Schofield et al., ; Thibeau, McFall, Wiebe, Anstey, & Dixon, ; Thow et al., ; Ward et al., , ; Wilkosc et al., ), and the rest evaluated samples of different disease states such as Alzheimer’s disease ( n = 4) (Lee et al., ; Lin et al., ; Nagata et al., , ), Parkinson’s disease ( n = 3) (Altmann et al., ; Bialecka et al., ; van der Kolk et al., ), cardiovascular diseases ( n = 2) (Swardfager et al., ; Szabo et al., ), obsessive‐compulsive disorder ( n = 2) (da Rocha et al., ; Tukel et al., ), schizophrenia and bipolar disorder ( n = 7) (Egan et al., ; Ho et al., ; Kim et al., ; Lee et al., ; Mezquida et al., ; Rybakowski et al., , ), traumatic brain injury ( n = 4) (Barbey et al., ; McAllister et al., ; Narayanan et al., ; Yu et al., ), depression ( n = 1) (Yin et al., ), multiple sclerosis ( n = 1) (Fera et al., ), breast cancer patients ( n = 1) (Ng et al., ), systemic lupus erythematosus ( n = 1) (Oroszi et al., ), and psychosis ( n = 1) (Aas et al., ).…”