Association between a polymorphism in the pseudoautosomal X-linked gene SYBL1 and bipolar affective disorder

In the past decade, several chromosomal regions have been analyzed for linkage with bipolar affective disorder (BPAD). There have been conflicting results regarding the involvement of X-chromosomal regions in harboring susceptibility genes for BPAD. Recently, a new candidate gene (SYBL1) for BPAD has been described on Xq28. SYBL1, which maps to the Xq pseudoautosomal region (PAR), encodes a member of the synaptobrevin family of proteins involved in synaptic vesicle docking, exocytosis, and membrane transport. A subsequent case-control association study, including 110 US-American patients with BPAD and 119 unrelated controls, investigated a potential etiological role of a novel polymorphism (G-->C transversion) in a regulatory region of the SYBL1 gene. In this analysis, the C allele showed a statistical trend to be more frequent in males with BPAD than in respective controls (P=0.06). This finding prompted us to verify whether a similar effect was also present in a larger German sample of 164 unrelated patients with BPAD (148 patients with BP I disorder, 16 patients with BP II disorder) and 267 controls. We observed a significantly increased frequency of genotypes homozygous for the C allele in females with BPAD in comparison with controls (P=0.017). Thus, our data strengthen the role of the SYBL1 gene as a candidate gene for BPAD.     

Functional assessment of a promoter polymorphism in S100B,a putative risk variant for bipolar disorder

Calcium‐binding protein S100B has been implicated in the pathology of bipolar affective disorder (BPAD) and schizophrenia (SZ). S100B protein levels are elevated in serum of patients with both disorders compared to controls. We previously reported genetic association of a SNP in the promoter of S100B, rs3788266, with a psychotic form of BPAD. To test for genotypic effects of rs3788266 in vivo, S100B serum protein levels were measured in 350 Irish and German subjects of known S100B genotype. The functional effect of rs3788266 on S100B promoter activity was studied using the luciferase reporter system in U373MG glioblastoma and SH‐SY5Y neuroblastoma cell lines. Allelic effects of rs3788266 on protein complex formation at the S100B promoter were investigated by an electrophoretic mobility shift assay. Higher mean serum S100B levels were associated with the risk G allele of rs3788266 in BPAD cases (P = 0.0001), unaffected relatives of BPAD cases (P < 0.0001) and unrelated controls (P < 0.0001). Consistent with the in vivo findings, luciferase gene expression was significantly increased in the presence of the G allele compared to the A allele in SH‐SY5Y (P = <0.0001), and in U373MG (P = <0.0008) cell lines. The binding affinity of both SH‐SY5Y and U373MG protein complexes for the S100B promoter was significantly stronger in the presence of G allele compared to the A allele promoter fragments. These data support rs3788266 as a functional promoter variant in the S100B gene where the presence of the G allele promotes increased gene expression and is associated with increased serum levels of the protein. © 2011 Wiley‐Liss, Inc.     

Genetics and Mental Retardation Syndromes,by Elisabeth M. Dykens,Robert M. Hodapp,and Brenda M. Finucane

Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case‐control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( ± five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over‐representation of genotype 5‐5 (P = 0.004) and allele 5 (P = 0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations. © 2002 Wiley‐Liss, Inc.     

Association study between two variants in the DOPA decarboxylase gene in bipolar and unipolar affective disorder

Irregularities of dopaminergic and serotonergic neurotransmission have been implicated in a variety of neuropsychiatric disorders. DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase, is an enzyme involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered as a candidate gene for affective disorders. Recently, two novel variants were reported in the DDC gene: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Subsequently, an association case-control study including 112 English patients and 80 Danish patients with bipolar affective disorder (BPAD) revealed a significant association with the 1-bp deletion. This finding prompted us to analyze whether this effect was also present in a larger and ethnically homogeneous sample of 228 unrelated German patients with BPAD (208 patients with BP I disorder, 20 patients with BP II disorder), 183 unrelated patients with unipolar affective disorder (UPAD), and 234 healthy control subjects. For both BPAD and UPAD we could not detect a genetic association with either variant. Thus, our results do not support an involvement of the 1-bp or 4-bp deletion within the DDC gene in the etiology of affective disorders.     

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: A multicenter association study

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n=172), family history alone (n=159), or high degree of diagnostic stability and a positive family history (n=131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:527–532, 1999. © 1999 Wiley-Liss, Inc.     

Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample.

Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study.     

Analysis of the pseudoautosomal X-linked gene SYBL1in bipolar affective disorder: description of a new candidate allele for psychiatric disorders

The absence of father-to-son transmission has been observed in a subset of families with bipolar disorder (BPD), suggestive of a susceptibility gene on the sex-linked portion of the X chromosome. This is supported by some genetic linkage studies that have provided evidence for a susceptibility locus near Xq28. We have analyzed one candidate gene on Xq28, SYBL1, which maps to the Xq pseudoautosomal region (PAR). SYBL1 encodes a member of the synaptobrevin family of proteins that is involved in synaptic vesicle docking and membrane transport. Genes in the PAR generally escape X-chromosome inactivation and have an active homolog on the Y chromosome, which would result in an increase in same-sex concordance in paternal transmitted traits. However, SYBL1 is neither expressed on the Y chromosome nor the inactive X chromosome and would therefore be expected to show typical sex-linked transmission. We have screened SYBL1 for mutations that could be tested as candidate alleles in the development of BPD. Following single-strand conformation polymorphism (SSCP) analysis and DNA sequencing, four single nucleotide polymorphisms were detected: a silent mutation at codon 108, two intron mutations without any obvious biological significance, and a G-->C transversion in the polypyrimidine tract at the 3' splice acceptor site preceding exon 8. This polymorphism, which creates a perfect 16/16 stretch of pyrimidines, was analyzed in 110 patients with BPD not selected for sex-linked transmission and 119 control subjects. The results show a statistical trend toward an increase in the frequency of the C allele in males with BPD but not females. Males: chi(2) = 3.46, 1 df, p =.06; Females: chi(2) =.20, 1 df, p =.66.     

Investigation of the human serotonin 6 (5‐HT6) receptor gene in bipolar affective disorder and schizophrenia

Serotonin (5‐hydroxytryptamine, 5‐HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5‐HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5‐HT₆ receptor gene to explore the contribution of this gene to the development of bipolar affective disorder and schizophrenia. Investigating 137 unrelated individuals (including 45 bipolar affective patients, 46 schizophrenic patients, and 46 unrelated controls), we identified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A/C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipolar patients (P=0.023 not corrected for multiple testing). This finding was followed up in an independent sample of 105 bipolar family trios using a family‐based association design. Fifty‐one transmissions could be examined. In 30 cases allele 267C and in 21 cases allele 267T were transmitted to the affected offspring. Although this result was far from statistical significance (transmission disequilibrium test=1.59, P=0.208), the limited number of possible transmissions may have prevented detection of smaller effects. Our preliminary data suggest that bipolar affective disorder may be associated with variation in the 5‐HT₆ gene. It will be important to extend the present analysis to larger samples. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:217–221, 2000. © 2000 Wiley‐Liss, Inc.     

Lack of association between polymorphisms in C4b‐binding protein and atypical haemolytic uraemic syndrome in the Spanish population

Dysregulation of the alternative pathway of complement activation, caused by mutations or polymorphisms in the genes encoding factor H, membrane co‐factor protein, factor I or factor B, is associated strongly with predisposition to atypical haemolytic uraemic syndrome (aHUS). C4b‐binding protein (C4BP), a major regulator of the classical pathway of complement activation, also has capacity to regulate the alternative pathway. Interestingly, the C4BP polymorphism p.Arg240His has been associated recently with predisposition to aHUS and the risk allele His240 showed decreased capacity to regulate the alternative pathway. Identification of novel aHUS predisposition factors has important implications for diagnosis and treatment in a significant number of aHUS patients; thus, we sought to replicate these association studies in an independent cohort of aHUS patients. In this study we show that the C4BP His240 allele corresponds to the C4BP*2 allele identified previously by isoelectric focusing in heterozygosis in 1·9–3·7% of unrelated Caucasians. Crucially, we found no differences between 102 unrelated Spanish aHUS patients and 128 healthy age‐matched Spanish controls for the frequency of carriers of the His240 C4BP allele. This did not support an association between the p.Arg240His C4BP polymorphism and predisposition to aHUS in the Spanish population. In a similar study, we also failed to sustain an association between C4BP polymorphisms and predisposition to age‐related macular degeneration, another disorder which is associated strongly with polymorphisms in factor H, and is thought to involve alternative pathway dysregulation.     

Association analysis of an (AC)n repeat polymorphism in the GABAB receptor gene and schizophrenia

The human γ‐aminobutyric acid type B (GABA_B) receptor gene is a candidate gene for schizophrenia due to its chromosomal location and neurobiologic roles. In the present study, association analyses of genetic polymorphisms of the GABA_B receptor gene with schizophrenia were carried out in 102 unrelated schizophrenic patients and 100 healthy controls, using a polymerase chain reaction‐based, single‐strand conformational polymorphism analysis. Although the Ala20Val and Gly489Ser mutations were not found in our samples, we found a novel polymorphism of (AC)n dinucleotide repeats located approximately 1.6 kb upstream from the translational start site. No significant difference in allele frequencies was found between controls and patients with schizophrenia (P = 0.0587) using the Monte Carlo method. Significant differences were found between controls and patients with continuous‐course schizophrenia (P = 0.0019), and between controls and patients with a positive family history of psychoses (P = 0.0015). These differences, however, were not significant after Bonferroni correction. These data did not support our hypothesis that polymorphisms of the GABA_B receptor gene may confer vulnerability for schizophrenia. © 2002 Wiley‐Liss, Inc.     

Absence of a significant linkage between Na+,K+‐ATPase subunit (ATP1A3 and ATP1B3) genotypes and bipolar affective disorder in the old‐order Amish

Previous studies provide evidence for a genetic component for susceptibility to bipolar affective disorder (BPAD) in the old‐order Amish population. El‐Mallakh and Wyatt [ 1995 : Biol Psychiatry 37:235–244] have suggested that the Na⁺,K⁺‐ATPase may be a candidate gene for BPAD. This study examines the relationship between BPAD in the old‐order Amish cohort and the Na⁺,K⁺‐ATPase α1 and β3 subunit genes (ATP1A3, ATP1B3). A total of 166 sibling pairs were analyzed for linkage via nonparametric methods. Suggestive levels of statistical significance were not reached in any stratification model for affective illness. Overall, the results do not support linkage of bipolar disorder to the Na⁺,K⁺‐ATPase alpha subunit gene (ATP1A3) and beta subunit gene (ATP1B3) in these old‐order Amish families and they show that these Na⁺,K⁺‐ATPase subunit genes are not major effect genes (≥fourfold increased genetic risk of disease) for BPAD in the old‐order Amish pedigrees. We cannot exclude other genetic variants of the Na⁺,K⁺‐ATPase hypothesis for BPAD, whereby other loci may modifying Na⁺,K⁺‐ATPase activity. © 2001 Wiley‐Liss, Inc.     

Association study between genetic variants at the PIP5K2A gene locus and schizophrenia and bipolar affective disorder.

Results from molecular and pharmacological studies point to involvement of the gene coding for the phosphatidylinositol-4-phosphate 5-kinase type II-alpha (PIP5K2A) in the development of schizophrenia and bipolar affective disorder (BPAD). The PIP5K2A gene locus, which is located on chromosomal region 10p12, has been implicated in the development of both disorders by independent linkage and association studies. On a cellular level, PIP5K2A is an enzyme component of the metabolism of inositol phosphate, which has been considered a potential target for the therapeutic action of lithium in BPAD patients. Given that the PIP5K2A gene is a promising candidate for the development of both disorders, we performed an association study between genetic variants at the PIP5K2A locus and 268 patients with schizophrenia, 260 patients with BPAD and 325 ethnically matched healthy controls. We failed to detect association to either disorder using PIP5K2A gene variants through single-marker and haplotype analysis. Therefore, our data does not support an involvement of the PIP5K2A locus in the etiology of either schizophrenia or BPAD in the German population.     

SYNGR1 is associated with schizophrenia and bipolar disorder in southern India

Chromosome 22q11–13 is one of the most consistent linkage regions for schizophrenia (SCZ) and bipolar disorder (BPAD). The SYNGR1 gene, which is associated with presynaptic vesicles in neuronal cells, is located on 22q13.1. We have previously identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. In the present study, a detailed analysis of this gene was performed in a case–control cohort (198 BPAD, 193 SCZ and 107 controls from southern India) to test for association with SCZ and BPAD. Sequence analysis of all exonic and flanking intronic regions of the SYNGR1 gene in 198 BPAD and 193 SCZ cases revealed a novel mutation Lsy99Glu (in one BPAD patient) and two other novel common polymorphisms [synonymous single nucleotide polymorphism (SNP—Ser97Ser) and an Asn ins/del] in the SYNGR1 gene. We also validated 9 out of 14 dbSNPs in our population. Case–control analysis revealed allelic (P=0.028–0.00007) association of five polymorphisms with SCZ and/or BPAD cases. Further, 3-SNP (with LD block 1 SNPs) and 2-SNP (with LD block 2 SNPs) haplotype analyses did not show any association with either SCZ or BPAD. Our results support SYNGR1 as a probable susceptibility gene for SCZ and BPAD. Also, the observed association of SYNGR1 with both SCZ and BPAD suggests the likely involvement of a common pathway in the etiology of these disorders.Electronic Supplementary Material Supplementary material is available for this article at     

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.     

Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders

Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.     

Association between the GABAA receptor α5 subunit gene locus (GABRA5) and bipolar affective disorder

Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABA_A receptor α5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:73–80, 1998. © 1998 Wiley-Liss, Inc.     

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European‐ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty‐two disease‐associated SNPs from the PGC‐BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10^?5, AUC = 0.60). In families with a high‐polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at‐risk youth, regardless of affected status, compared to unrelated controls (GEE‐χ² = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease‐associated variants than unrelated controls and first‐degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

     

RP1L1 Variants are Associated with a Spectrum of Inherited Retinal Diseases Including Retinitis Pigmentosa and Occult Macular Dystrophy

In one consanguineous family with retinitis pigmentosa (RP), a condition characterized by progressive visual loss due to retinal degeneration, homozygosity mapping, and candidate gene sequencing suggested a novel locus. Exome sequencing identified a homozygous frameshifting mutation, c.601delG, p.Lys203Argfs*28, in RP1L1 encoding RP 1‐like1, a photoreceptor‐specific protein. A screen of a further 285 unrelated individuals with autosomal recessive RP identified an additional proband, homozygous for a missense variant, c.1637G>C, p.Ser546Thr, in RP1L1. A distinct retinal disorder, occult macular dystrophy (OCMD) solely affects the central retinal cone photoreceptors and has previously been reported to be associated with variants in the same gene. The association between mutations in RP1L1 and the disorder OCMD was explored by screening a cohort of 28 unrelated individuals with the condition; 10 were found to harbor rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1L1 missense variants. Analysis of family members revealed many unaffected relatives harboring the same variant. Linkage analysis excluded the possibility of a recessive mode of inheritance, and sequencing of RP1, a photoreceptor protein that interacts with RP1L1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP1L1 in human retinal physiology and disease.