Integrative genetics of behavior with high throughput technologies

National Institute On Alcohol Abuse And Alcoholism

Investigators

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Abstract

Identification of functional loci is key to the Maps to Mechanisms to Medicine (M2M2M) paradigm articulated by the International Common Disease alliance (ICDA) and that has been LNG's focus since 1992. Alcohol Use disorder (AUD) and Substance Use Disorders (SUD) are moderately heritable but most of the genetic variance is unexplained. We discovered several functional loci with roles in AUD and SUD via founder populations, people at risk due to exposures, model organisms and intermediate phenotypes closer to gene action. Model organisms, including artificially selected mice and rats, and cell models, are used for gene discovery, to identify functional loci, to elucidate genetic architecture, and for validation. GWAS, transcriptomics and exome sequencing are global approaches to gene discovery independent of prior hypotheses. VIA GWAS, we found loci for subjective response to alcohol (Lai et al, 2020), AUD (Lai et al, 2021), AUD treatment response (Biernacka, 2021, and alcohol cirrhosis (Schwantes-An et al, 2020). Via transcriptomics we advanced understanding of glia in SUDs (De Biase, 2017), cirrhosis (Guillot et al, 2021), and developmental effects of nicotine (Jung, 2016). Via transcriptomics we identified pathways, and genes, contributing to intrinsic differences in ovarian steroid response in women with Premenstrual Dysphoric Disorder and Perimenopausal Depression (Dubey, Mol Psych, 2016; Rudzinskas, Mol Psych, 2020; Li et al, Mol Psych 2021). We have made progress in identifying functional loci contributing to AUD. OPRM1 Asn40Asp (Bergen et al, 1997) was found to be functional and linked to AUD naltrexone treatment response (Anton et al, 2008). We described a common, functional SNP in the serotonin transporter (Hu et al, 2007) that enhances understanding of OCD, neuroimaging responses to emotion, and gene x stress interactions. Common HTR2C Ser23Cys (Lappalainen et al, 1999, Okada et al, 2004) and HTR2A Asn452His variants (Ozaki et al, 1997) were found, shown functional, and linked to behavior. We found that a functional DRD2 promoter variant influences antipsychotic response (Lencz et al, 2006). We traced linkages of functional and haplotypes of NPY (Zhu et al, 2008), GCH1 (Tegeder et al, 2006) and DISC1 (Hodgkinson et al, 2004) to emotionality, schizophrenia and pain. We found an HTR2B stop codon that is relatively common in Finns, absent in others, and associated with but not determinant for impulsive behavior. The stop codon cosegregated with ASPD and AUD in families and the mouse Htr2b knockout was impulsive and high in novelty seeking and novelty response. (Bevilacqua et al, Nature, 2010). The low expression Neuropeptide Y (NPY) haplotype increased anxiety and emotionality but had stronger effects on molecules (NPY RNA and protein) and intermediate phenotypes (brain imaging responses to emotion and pain/stress) (Zhou et al, Nature, 2008). Intermediate phenotypes augment analysis of behavior (Ducci and Goldman). We proposed a multidimensional Addictions Neuroclinical Assessment based on the addiction cycle (Kwako et al, Biol Psych) and recovered the theorized three factor structure in the intramural AUD sample (Kwako et al, AJP, 2019). The imaging genetics paradigm we helped initiate (Heinz et al, 2000; Hariri et al, 2002; Egan et al, 2001; 2003; Zubieta et al, 2003) led to groundbreaking findings. We found that CHRNA5 Asn398, an allele altering nicotine addiction risk, weakens brain connectivities including a Dorsal Anterior Cingulate/Ventral Striatal circuit predictive of craving (Hong et al, 2010). Clinical subphenotyping enabled linkage of HTR1B to antisocial alcoholism (Lappalainen et al, 1998), serotonin transporter (SLCA4) to anxiety (Mazzanti et al; Hariri et al), BDNF Val66Met to episodic memory (Egan et al, cell, 2003), and GTP cyclohydrolase to chronic pain and experimental pain response (Tegeder et al, 2006). Frontal cognitive deficit is a risk factor in schizophrenia, AUD and other diseases. Dopamine generally enhances prefrontal cortical efficiency. Met158, a common COMT variant, leads to four-fold reduction in COMT activity. It is thus a candidate allele for cognitive function via effect on frontal dopamine. We found an allele-dosage relationship of Met158 to frontal cognitive function and diminished cortical efficiency (Egan et al, 2001). The effect on cognition is seen in populations differing in baseline cognitive function: schizophrenia, head injury (Lipsky et al, 2005, 2011), & controls (Malhotra et al, 2002, 2009). We proposed that Val158 has a counter-advantage: stress resiliency. In two populations Met158 predicted anxiety in women and decreased frontal EEG coherence (Enoch et al, 2003), and Met158 was associated with lower resiliency to pain/stress (Zubieta et al, Science, 2003; Diatchenko et al, 2005, 2006). We have extended knowledge of GxE effects of stress related genes such as COMT, NPY, SLC6A4 and SLC6A4 in many studies using both behavioral and endocrine outcomes (Lovallo et al 2015, 2016). A functional polymorphism of Fatty Acid Amide Hydrolase (FAAH) specifically predicts placebo response to pain (Pecina et al, 2014). The Chr 4 GABAA gene cluster was implicated in AUD by family linkage (Long et al, 1998), an effect that appears anxiety-modulated (Enoch et al, 2006). Another GABAA gene cluster implicated in AUD and alcohol response is on Chr 5 (Radel et al, 2005). GABRA6 has a missense variant associated with alcohol dependence and response to alcohol and diazepam (Iwata et al, 2005). A family linkage scan yielded genome-wide significant linkage of CRF-BP to an AUD-associated EEG trait and this was supported by association in two populations (Enoch et al, 2008). GWAS of EEG (Hodgkinson et al, PNAS, 2010) in Plains Indians detected genome-wide significant loci (Hodgkinson et al, PNAS 2010). Via GWAS, a schizophrenia risk locus was identified (Lencz et al, Nat Comm, 2013). Founder, phenotypically extreme, and exposed populations enhance power to detect genes. Our Finnish sample was ascertained from a founder population and via criminal AUD probands. An African American substance dependence sample revealed GxE of childhood trauma and HTTLPR in suicidality (Roy et al, 2007). Stress and poverty, but not African ancestry, predicted addictions (Ducci et al, 2009). An MAOA VNTR previously linked to dyscontrol via stress interaction was linked to AUD and ASPD in Native American women, half who were sexually abused as children (Ducci et al, 2008). A strong interaction between a MAOA VNTR and testosterone on aggression was observed (Sjoberg et al, 2008). Deep sequencing detected a population-specific HTR2B Stop codon in arousal and AUD (Bevilacqua et al, Nature, 2010). We exome-sequenced an artificially selected animal model for alcoholism, the P/NP rat, and discovered a stop codon in metabotropic glutamate receptor 2 (Grm2) that leads to alcohol preference (Zhou et al, 2013). The Grm2 Stop codon is common (0.08) or fixed in parental Wistar rats, depending on source. It leads to uncompensated changes in glutamate function. It was genetically fixed by artificial selection in the alcohol preferring and non-preferring rats illustrating the power of such strains for gene discovery. Via parallel exome sequencing in selected strains and people we are identifying genes involved in drug reward and withdrawal. As facilitated by a NIDA RFA leading to two U01 grants we identified new loci altering drug preference in rat and Drosophila. We found the same Grm2 stop codon in a Wistar-derived cocaine model. We found 7 genome wide significant loci accounting for 2/3rds of variance in novelty induced hyperlocomotion, a hyperarousal model predicting drug use (Zhou et al, PNAS, 2019).